OPDIVO

1 INDICATIONS AND USAGE OPDIVO is a programmed death receptor-1 (PD-1)-blocking antibody indicated for the treatment of: Melanoma • adult and pediatric (12 years and older) patients with unresectable or metastatic melanoma, as a single agent or in combination with ipilimumab. (1.1) • for the adjuvant treatment of adult and pediatric patients 12 years and older with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma. (1.2) Non-Small Cell Lung Cancer (NSCLC) • adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer in the neoadjuvant setting, in combination with platinum-doublet chemotherapy. (1.3) • adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer and no known EGFR mutations or ALK rearrangements, for neoadjuvant treatment, in combination with platinum-doublet chemotherapy, followed by single-agent OPDIVO as adjuvant treatment after surgery. (1.4) • adult patients with metastatic non-small cell lung cancer expressing PD‑L1 (≥1%) as determined by an FDA-authorized test, with no EGFR or ALK genomic tumor aberrations, as first-line treatment in combination with ipilimumab. (1.5) • adult patients with metastatic or recurrent non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations as first-line treatment, in combination with ipilimumab and 2 cycles of platinum-doublet chemotherapy. (1.5) • adult patients with metastatic non-small cell lung cancer and progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO. (1.5) Malignant Pleural Mesothelioma • adult patients with unresectable malignant pleural mesothelioma, as first-line treatment in combination with ipilimumab. (1.6) Renal Cell Carcinoma (RCC) • adult patients with intermediate or poor risk advanced renal cell carcinoma, as a first-line treatment in combination with ipilimumab. (1.7) • adult patients with advanced renal cell carcinoma, as a first-line treatment in combination with cabozantinib. (1.7) • adult patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy. (1.7) Classical Hodgkin Lymphoma (cHL) • adult and pediatric (12 years and older) patients with previously untreated, Stage III or IV classical Hodgkin lymphoma in combination with doxorubicin, vinblastine, and dacarbazine (AVD). (1.8) • adult patients with classical Hodgkin lymphoma that has relapsed or progressed after: (1.8) • autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin, or • 3 or more lines of systemic therapy that includes autologous HSCT. Squamous Cell Carcinoma of the Head and Neck (SCCHN) • adult patients with recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on or after a platinum-based therapy. (1.9) Urothelial Carcinoma • adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC. (1.10) • adult patients with unresectable or metastatic urothelial carcinoma, as first-line treatment in combination with cisplatin and gemcitabine. (1.10) • adult patients with locally advanced or metastatic urothelial carcinoma who: • have disease progression during or following platinum-containing chemotherapy. • have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. (1.10) Colorectal Cancer • adult and pediatric (12 years and older) patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC) in combination with ipilimumab. (1.11) • adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. ( 1.11 ) Hepatocellular Carcinoma (HCC) • adult patients with unresectable or metastatic hepatocellular carcinoma (HCC), as a first-line treatment in combination with ipilimumab. (1.12) • in combination with ipilimumab in adult patients with unresectable or metastatic HCC who have been previously treated with sorafenib. ( 1.12 ) Esophageal Cancer • adult patients with completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease, who have received neoadjuvant chemoradiotherapy (CRT). (1.13) • adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma as first-line treatment in combination with fluoropyrimidine- and platinum‑containing chemotherapy whose tumors express PD-L1 (≥1). (1.13) • adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma as first-line treatment in combination with ipilimumab whose tumors express PD-L1 (≥1). (1.13) • adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy. (1.13) Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma • adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma whose tumors express PD-L1 (≥1) in combination with fluoropyrimidine- and platinum-containing chemotherapy. (1.14) 1.1 Unresectable or Metastatic Melanoma OPDIVO, as a single agent or in combination with ipilimumab, is indicated for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic melanoma. 1.2 Adjuvant Treatment of Melanoma OPDIVO is indicated for the adjuvant treatment of adult and pediatric patients 12 years and older with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma. 1.3 Neoadjuvant Treatment of Resectable Non-Small Cell Lung Cancer OPDIVO, in combination with platinum-doublet chemotherapy, is indicated as neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer (NSCLC). 1.4 Neoadjuvant and Adjuvant Treatment of Resectable Non-Small Cell Lung Cancer OPDIVO, in combination with platinum-doublet chemotherapy, is indicated for the neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) NSCLC and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements, followed by single-agent OPDIVO as adjuvant treatment after surgery. 1.5 Metastatic Non-Small Cell Lung Cancer • OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with metastatic NSCLC whose tumors express PD-L1 (≥1%) as determined by an FDA-authorized test [see Dosage and Administration (2.1) ] , with no EGFR or ALK genomic tumor aberrations. • OPDIVO, in combination with ipilimumab and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent NSCLC, with no EGFR or ALK genomic tumor aberrations. • OPDIVO is indicated for the treatment of adult patients with metastatic NSCLC with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO. 1.6 Malignant Pleural Mesothelioma OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma. 1.7 Advanced Renal Cell Carcinoma • OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced RCC. • OPDIVO, in combination with cabozantinib, is indicated for the first-line treatment of adult patients with advanced RCC. • OPDIVO, as a single agent, is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy. 1.8 Classical Hodgkin Lymphoma • OPDIVO, in combination with doxorubicin, vinblastine, and dacarbazine (AVD), is indicated for the treatment of adult and pediatric patients 12 years and older with previously untreated, Stage III or IV classical Hodgkin lymphoma (cHL). • OPDIVO, as a single agent, is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after: • autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin, or • 3 or more lines of systemic therapy that includes autologous HSCT. 1.9 Squamous Cell Carcinoma of the Head and Neck OPDIVO is indicated for the treatment of adult patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy. 1.10 Urothelial Carcinoma OPDIVO is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC [see Clinical Studies (14.10) ] . OPDIVO, in combination with cisplatin and gemcitabine, is indicated for the first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma. OPDIVO is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who: • have disease progression during or following platinum-containing chemotherapy. • have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. 1.11 Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer • OPDIVO, in combination with ipilimumab, is indicated for the treatment of adult and pediatric patients 12 years and older with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC) . • OPDIVO, as a single agent, is indicated for the treatment of adult and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. 1.12 Hepatocellular Carcinoma • OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with unresectable or metastatic hepatocellular carcinoma (HCC). • OPDIVO, in combination with ipilimumab, is indicated for the treatment of adult patients with unresectable or metastatic HCC who have been previously treated with sorafenib. 1.13 Esophageal Cancer • OPDIVO is indicated for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in adult patients who have received neoadjuvant chemoradiotherapy (CRT). • OPDIVO, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) whose tumors express PD-L1 (≥1) [see Dosage and Administration (2.1) ] . • OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC) whose tumors express PD-L1 (≥1) [see Dosage and Administration (2.1) ] . • OPDIVO is indicated for the treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy. 1.14 Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma OPDIVO, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma whose tumors express PD-L1 (≥1) [see Dosage and Administration (2.1) ] .

2 DOSAGE AND ADMINISTRATION • Administer by intravenous infusion after dilution based upon recommended infusion rate for each indication. (2) • Unresectable or metastatic melanoma • Adult and pediatric patients weighing 40 kg or greater: 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2) • Pediatric patients weighing less than 40 kg: 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks. (2.2) • Adult and pediatric patients weighing 40 kg or greater: 1 mg/kg followed by ipilimumab 3 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2) • Pediatric patients weighing less than 40 kg: 1 mg/kg followed by ipilimumab 3 mg/kg on the same day every 3 weeks for 4 doses, then 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks. (2.2) • Adjuvant treatment of melanoma • Adult and pediatric patients weighing 40 kg or greater: 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2) • Pediatric patients weighing less than 40 kg: 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks. (2.2) • Neoadjuvant treatment of resectable (tumors ≥4 cm or node positive) non-small cell lung cancer • 360 mg with platinum-doublet chemotherapy on the same day every 3 weeks for 3 cycles. (2.2) • Neoadjuvant and adjuvant treatment of resectable non-small cell lung cancer • 360 mg with platinum-doublet chemotherapy on the same day every 3 weeks for up to 4 cycles, then continued as single-agent OPDIVO 480 mg every 4 weeks after surgery for up to 13 cycles (~1 year). (2.2) • Metastatic non-small cell lung cancer • 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks. (2.2) • 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy. (2.2) • 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2) • Malignant pleural mesothelioma • 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks. (2.2) • Advanced renal cell carcinoma • 3 mg/kg followed by ipilimumab 1 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2) • 240 mg every 2 weeks or 480 mg every 4 weeks administered in combination with cabozantinib 40 mg once daily without food. (2.2) • 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2) • Classical Hodgkin lymphoma • Adult and pediatric patients weighing 40 kg or greater: 240 mg in combination with doxorubicin, vinblastine, and dacarbazine (AVD) every 2 weeks for 6 cycles. (2.2) • Pediatric patients weighing less than 40 kg: 3 mg/kg in combination with AVD every 2 weeks for 6 cycles. (2.2) • 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2) • Recurrent or metastatic squamous cell carcinoma of the head and neck • 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2) • Adjuvant treatment of urothelial carcinoma • 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2) • First-line unresectable or metastatic urothelial carcinoma • 360 mg every 3 weeks with cisplatin and gemcitabine on the same day for up to 6 cycles, then 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2) • Previously treated locally advanced or metastatic urothelial carcinoma • 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2) • Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer • Adult and pediatric patients weighing 40 kg or greater: 240 mg followed by ipilimumab 1 mg/kg on the same day every 3 weeks for a maximum of 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks. ( 2.2 ) • Pediatric patients weighing less than 40 kg: 3 mg/kg followed by ipilimumab 1 mg/kg on the same day every 3 weeks for a maximum of 4 doses, then 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks. ( 2.2 ) • Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following prior treatment for metastatic disease. • Adult and pediatric patients weighing 40 kg or greater: 240 mg every 2 weeks or 480 mg every 4 weeks. ( 2.2 ) • Pediatric patients weighing less than 40 kg: 3 mg/kg every 2 weeks. ( 2.2 ) • Hepatocellular carcinoma • 1 mg/kg followed by ipilimumab 3 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2) • Adjuvant treatment of resected esophageal or gastroesophageal cancer • 240 mg every 2 weeks or 480 mg every 4 weeks for total treatment duration of 1 year. (2.2) • Esophageal squamous cell carcinoma • 240 mg every 2 weeks or 480 mg every 4 weeks in combination with chemotherapy regimen of fluoropyrimidine- and platinum-containing chemotherapy. (2.2) • 3 mg/kg every 2 weeks or 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks. (2.2) • 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2) • Gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC, GEJC, or EAC) • 360 mg every 3 weeks with fluoropyrimidine- and platinum-containing chemotherapy every 3 weeks. (2.2) • 240 mg every 2 weeks with fluoropyrimidine- and platinum-containing chemotherapy every 2 weeks. (2.2) • See full Prescribing Information for preparation and administration instructions and dosage modifications for adverse reactions. 2.1 Patient Selection Information on FDA-authorized tests for patient selection is available at: https://www.fda.gov/CompanionDiagnostics Non-Small Cell Lung Cancer • Select patients with metastatic NSCLC for treatment with OPDIVO in combination with ipilimumab based on PD-L1 expression [see Clinical Studies (14.5) ] . Esophageal Cancer • Select patients with unresectable advanced or metastatic ESCC for treatment with OPDIVO in combination with fluoropyrimidine- and platinum-containing chemotherapy based on PD-L1 expression [see Clinical Studies (14.13) ] . • Select patients with unresectable advanced or metastatic ESCC for treatment with OPDIVO in combination with ipilimumab based on PD-L1 expression [see Clinical Studies (14.13) ] . • An FDA-authorized companion diagnostic for the detection of PD-L1 expression in patients with advanced or metastatic ESCC is not available. Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma • Select patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma for treatment with OPDIVO in combination with fluoropyrimidine- and platinum-containing chemotherapy based on PD-L1 expression [see Clinical Studies (14.14) ] . • An FDA-authorized companion diagnostic for the detection of PD-L1 expression in patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma is not available . 2.2 Recommended Dosage The recommended dosages of intravenous OPDIVO as a single agent are presented in Table 1. Administer OPDIVO as a 30-minute intravenous infusion [see Dosage and Administration (2.4) ] . Table 1: Recommended Dosages for Intravenous OPDIVO as a Single Agent Indication Recommended OPDIVO Dosage Duration of Therapy Metastatic non-small cell lung cancer 240 mg every 2 weeks or 480 mg every 4 weeks Until disease progression or unacceptable toxicity Advanced renal cell carcinoma Classical Hodgkin lymphoma Squamous cell carcinoma of the head and neck Locally advanced or metastatic urothelial carcinoma Esophageal squamous cell carcinoma Unresectable or metastatic melanoma Adult patients and pediatric patients aged 12 years and older and weighing 40 kg or more: 240 mg every 2 weeks or 480 mg every 4 weeks Until disease progression or unacceptable toxicity Pediatric patients aged 12 years and older and weighing less than 40 kg: 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks Adjuvant treatment of melanoma Adult patients and pediatric patients aged 12 years and older and weighing 40 kg or more: 240 mg every 2 weeks or 480 mg every 4 weeks Until disease recurrence or unacceptable toxicity for up to 1 year Pediatric patients aged 12 years and older and weighing less than 40 kg: 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks Adjuvant treatment of urothelial carcinoma (UC) 240 mg every 2 weeks or 480 mg every 4 weeks Until disease recurrence or unacceptable toxicity for up to 1 year Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following prior treatment for metastatic disease Adult patients and pediatric patients aged 12 years and older and weighing 40 kg or more: 240 mg every 2 weeks or 480 mg every 4 weeks Until disease progression or unacceptable toxicity Pediatric patients aged 12 years and older and weighing less than 40 kg: 3 mg/kg every 2 weeks Adjuvant treatment of resected esophageal or gastroesophageal junction cancer 240 mg every 2 weeks or 480 mg every 4 weeks Until disease progression or unacceptable toxicity for a total treatment duration of 1 year The recommended dosages of OPDIVO in combination with other therapeutic agents are presented in Table 2. Administer OPDIVO on the same day as other therapeutic agents. Refer to the respective Prescribing Information for each therapeutic agent administered in combination with OPDIVO for the recommended dosage information, as appropriate. Table 2: Recommended Dosages of Intravenous OPDIVO in Combination with Other Therapeutic Agents Indication Recommended OPDIVO Dosage Duration of Therapy Unresectable or metastatic melanoma 1 mg/kg every 3 weeks with ipilimumab 3 mg/kg In combination with ipilimumab for a maximum of 4 doses or until unacceptable toxicity, whichever occurs earlier Adult patients and pediatric patients aged 12 years and older and weighing 40 kg or more: 240 mg every 2 weeks or 480 mg every 4 weeks After completing 4 doses of combination therapy, administer as single agent until disease progression or unacceptable toxicity Pediatric patients aged 12 years and older and weighing less than 40 kg: 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks Neoadjuvant treatment of resectable non-small cell lung cancer 360 mg every 3 weeks with platinum-doublet chemotherapy on the same day every 3 weeks In combination with platinum-doublet chemotherapy for 3 cycles Neoadjuvant and adjuvant treatment of resectable non-small cell lung cancer Neoadjuvant: 360 mg every 3 weeks with platinum-doublet chemotherapy on the same day every 3 weeks Neoadjuvant treatment in combination with chemotherapy for up to 4 cycles or until disease progression or unacceptable toxicity, followed by adjuvant treatment with OPDIVO as a single agent after surgery for up to 13 cycles (approximately 1 year) or until disease recurrence or unacceptable toxicity Adjuvant: 480 mg every 4 weeks Metastatic non-small cell lung cancer expressing PD‑L1 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression Metastatic or recurrent non-small cell lung cancer 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks and histology-based platinum‑doublet chemotherapy every 3 weeks In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression In combination with histology-based platinum‑doublet chemotherapy for up to 2 cycles Malignant pleural mesothelioma 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression Advanced renal cell carcinoma 3 mg/kg every 3 weeks with ipilimumab 1 mg/kg In combination with ipilimumab for 4 doses 240 mg every 2 weeks or 480 mg every 4 weeks After completing 4 doses of combination therapy with ipilimumab, administer as single agent until disease progression or unacceptable toxicity 240 mg every 2 weeks or 480 mg every 4 weeks Administer OPDIVO in combination with cabozantinib 40 mg orally once daily without food OPDIVO : Until disease progression, unacceptable toxicity , or up to 2 years Cabozantinib: Until disease progression or unacceptable toxicity First-line unresectable or metastatic urothelial carcinoma 360 mg every 3 weeks Administer OPDIVO in combination with cisplatin and gemcitabine on the same day every 3 weeks In combination with cisplatin and gemcitabine for up to 6 cycles 240 mg every 2 weeks or 480 mg every 4 weeks After completing up to 6 cycles of combination therapy, administer as single agent until disease progression, unacceptable toxicity, or up to 2 years from first dose Previously untreated classical Hodgkin lymphoma Adult patients and pediatric patients aged 12 years and older and weighing 40 kg or more: 240 mg every 2 weeks In combination with doxorubicin, vinblastine, and dacarbazine (AVD) for 6 cycles. GCSF administration is recommended starting with cycle 1. Pediatric patients aged 12 years and older and weighing less than 40 kg: 3 mg/kg every 2 weeks Microsatellite instability-high (MSI‑H) or mismatch repair deficient (dMMR) metastatic colorectal cancer Adult patients and pediatric patients aged 12 years and older and weighing 40 kg or more: 240 mg every 3 weeks with ipilimumab 1 mg/kg In combination with ipilimumab for a maximum of 4 doses Pediatric patients aged 12 years and older and weighing less than 40 kg: 3 mg/kg every 3 weeks with ipilimumab 1 mg/kg Adult patients and pediatric patients aged 12 years and older and weighing 40 kg or more: 240 mg every 2 weeks or 480 mg every 4 weeks After completing a maximum of 4 doses of combination therapy, administer as single agent until disease progression or unacceptable toxicity , or up to 2 years Pediatric patients aged 12 years and older and weighing less than 40 kg: 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks Hepatocellular carcinoma 1 mg/kg every 3 weeks with ipilimumab 3 mg/kg In combination with ipilimumab for a maximum of 4 doses 240 mg every 2 weeks or 480 mg every 4 weeks After completing a maximum of 4 doses of combination therapy, administer as single agent until disease progression, unacceptable toxicity, or up to 2 years Esophageal squamous cell carcinoma 240 mg every 2 weeks or 480 mg every 4 weeks Administer OPDIVO in combination with fluoropyrimidine- and platinum‑containing chemotherapy OPDIVO: Until disease progression, unacceptable toxicity, or up to 2 years Chemotherapy: Until disease progression or unacceptable toxicity 3 mg/kg every 2 weeks or 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks In combination with ipilimumab until disease progression, unacceptable toxicity, or up to 2 years Gastric cancer, Gastroesophageal junction cancer, and Esophageal adenocarcinoma 240 mg every 2 weeks with fluoropyrimidine- and platinum‑containing chemotherapy every 2 weeks or 360 mg every 3 weeks with fluoropyrimidine- and platinum‑containing chemotherapy every 3 weeks Until disease progression, unacceptable toxicity, or up to 2 years 2.3 Dosage Modifications No dose reduction for OPDIVO is recommended. In general, withhold OPDIVO for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue OPDIVO for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids. Dosage modifications for OPDIVO or OPDIVO in combination for adverse reactions that require management different from these general guidelines are summarized in Table 3 and Table 4. When OPDIVO is administered in combination with ipilimumab, withhold or permanently discontinue both ipilimumab and OPDIVO for an adverse reaction meeting these dose modification guidelines. Table 3: Recommended Dosage Modifications for Adverse Reactions a Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids. b If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue OPDIVO based on recommendations for hepatitis with no liver involvement. c Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved. ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal Adverse Reaction Severity Dosage Modification Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) ] Pneumonitis Grade 2 Withhold a Grades 3 or 4 Permanently discontinue Colitis For colitis in patients treated with combination therapy with ipilimumab, see Table 4. Grade 2 or 3 Withhold a Grade 4 Permanently discontinue Hepatitis with no tumor involvement of the liver For liver enzyme elevations in patients treated with combination therapy with ipilimumab, see Table 4. AST/ALT increases to >3 and ≤8 times ULN or Total bilirubin increases to >1.5 and ≤3 times ULN. Withhold a AST or ALT increases to >8 times ULN or Total bilirubin increases to >3 times ULN. Permanently discontinue Hepatitis with tumor involvement of the liver b For liver enzyme elevations in patients treated with combination therapy with ipilimumab, see Table 4. Baseline AST/ALT is >1 and ≤3 times ULN and increases to >5 and ≤10 times ULN or Baseline AST/ALT is >3 and ≤5 times ULN and increases to >8 and ≤10 times ULN. Withhold a AST/ALT increases to >10 times ULN or Total bilirubin increases to >3 times ULN. Permanently discontinue Endocrinopathies c Grade 3 or 4 Withhold until clinically stable or permanently discontinue depending on severity Nephritis with Renal Dysfunction Grade 2 or 3 increased blood creatinine Withhold a Grade 4 increased blood creatinine Permanently discontinue Exfoliative Dermatologic Conditions Suspected SJS, TEN, or DRESS Withhold Confirmed SJS, TEN, or DRESS Permanently discontinue Myocarditis Grades 2, 3, or 4 Permanently discontinue Neurological Toxicities Grade 2 Withhold a Grade 3 or 4 Permanently discontinue Other Adverse Reactions Infusion-Related Reactions [see Warnings and Precautions (5.2) ] Grade 1 or 2 Interrupt or slow the rate of infusion Grade 3 or 4 Permanently discontinue Table 4: Recommended Dosage Modifications for Adverse Reactions in Patients Treated with Combination Therapy a Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of last dose or inability to reduce prednisone to 10 mg per day (or equivalent) or less within 12 weeks of initiating steroids. b If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue OPDIVO in combination with ipilimumab based on recommendations for hepatitis with no liver involvement. c Consider corticosteroid therapy for hepatic adverse reactions if OPDIVO is withheld or discontinued when administered in combination with cabozantinib or AVD. d After recovery, rechallenge with OPDIVO, cabozantinib, and AVD may be considered. If rechallenging with cabozantinib or doxorubicin and vinblastine with or without OPDIVO, refer to cabozantinib or doxorubicin and vinblastine Prescribing Information. e Refer to doxorubicin, vinblastine, and dacarbazine Prescribing Information. Treatment Adverse Reaction Severity Dosage Modification OPDIVO in combination with ipilimumab Colitis Grade 2 Withhold a Grade 3 or 4 Permanently discontinue Hepatitis with no tumor involvement of the liver or Hepatitis with tumor involvement of the liver/non-HCC AST/ALT increases to >3 times ULN and ≤5 times ULN or Total bilirubin increases to ≥1.5 and ≤3 times ULN. Withhold a AST or ALT >5 times ULN or Total bilirubin >3 times ULN. Permanently discontinue Hepatitis with tumor involvement of the liver b /HCC Baseline AST/ALT is >1 and ≤3 times ULN and increases to >5 and ≤10 times ULN or Baseline AST/ALT is >3 and ≤5 times ULN and increases to >8 and ≤10 times ULN. Withhold a AST/ALT increases to >10 times ULN or Total bilirubin increases to >3 times ULN. Permanently discontinue OPDIVO in combination with cabozantinib Liver enzyme elevations ALT or AST >3 times ULN but ≤10 times ULN with concurrent total bilirubin <2 times ULN Withhold c both OPDIVO and cabozantinib until adverse reactions recover d to Grades 0‑1 ALT or AST >10 times ULN or >3 times ULN with concurrent total bilirubin ≥2 times ULN Permanently discontinue c both OPDIVO and cabozantinib OPDIVO in combination with AVD e Liver enzyme elevations ALT or AST >3 times ULN but ≤8 times ULN Withhold c OPDIVO until adverse reactions recover d to Grades 0-1 ALT or AST >8 times ULN or >3 times ULN with concurrent total bilirubin >2 times ULN Permanently discontinue c OPDIVO Bilirubin >2 times ULN but ≤5 times ULN Consider dose reduction of doxorubicin and vinblastine. e Bilirubin >5 times ULN Permanently discontinue c OPDIVO. Consider holding doxorubicin and vinblastine. e Neutropenia Grade 3 or 4 Administer G-CSF prophylaxis for subsequent cycles. Consider additional doses for protracted Grade 4 neutropenia. Febrile neutropenia, infection Grade 3 or 4 Consider holding treatment until recovery to ≤ Grade 2. Administer G-CSF prophylaxis with subsequent cycles. Peripheral neuropathy Grade 3 Consider withholding vinblastine and restarting at a reduced dose as indicated. If OPDIVO-related, withhold OPDIVO until improves to Grade 2. Grade 4 Permanently discontinue vinblastine. If OPDIVO-related, permanently discontinue OPDIVO. 2.4 Preparation and Administration Visually inspect for particulate matter and discoloration. OPDIVO is a clear to opalescent, colorless to pale-yellow solution. Discard if cloudy, discolored, or contains extraneous particulate matter other than a few translucent-to-white, proteinaceous particles. Do not shake. Preparation • Withdraw the required volume of OPDIVO and transfer into an intravenous container. • Dilute OPDIVO with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to prepare an infusion with a final concentration ranging from 1 mg/mL to 10 mg/mL. The total volume of infusion must not exceed 160 mL. • For adult and pediatric patients with body weight 40 kg or greater, do not exceed a total volume of infusion of 160 mL . • For adult and pediatric patients with body weight less than 40 kg, do not exceed a total volume of infusion of 4 mL/kg of body weight. • Mix diluted solution by gentle inversion. Do not shake. • Discard partially used vials or empty vials of OPDIVO. • The product does not contain a preservative. • After preparation, store the diluted solution either: • at room temperature at 20°C to 25°C (68°F to 77°F) and room light for no more than 8 hours from the time of preparation to end of the infusion. Discard diluted solution if not used within 8 hours from the time of preparation; or • under refrigeration at 2°C to 8°C (36°F to 46°F) and protected from light for no more than 7 days from the time of preparation to end of infusion. Discard diluted solution if not used within 7 days from the time of preparation. • Do not freeze. Administration • Administer the infusion, after dilution, over 30 minutes through an intravenous line containing a sterile, nonpyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 1.2 micrometer). • Administer OPDIVO in combination with other therapeutic agents as follows: Combination Therapy Ipilimumab Administer OPDIVO first, followed by the other therapeutic agent(s). Platinum-Doublet Chemotherapy Ipilimumab and Platinum-Doublet Chemotherapy Fluoropyrimidine- and Platinum- Containing Chemotherapy Doxorubicin, Vinblastine, and Dacarbazine (AVD) Administer OPDIVO last. • Use separate infusion bags and filters for each infusion. • Flush the intravenous line at end of infusion. • Do not co-administer other drugs through the same intravenous line.

4 CONTRAINDICATIONS None. • None. (4)

5 WARNINGS AND PRECAUTIONS • Immune-Mediated Adverse Reactions: (5.1) • Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis and hepatotoxicity, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, and immune-mediated nephritis and renal dysfunction. • Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. • Withhold or permanently discontinue based on severity and type of reaction. (2.3) • Infusion-related reactions: Interrupt, slow the rate of infusion, or permanently discontinue OPDIVO based on severity of reaction. (5.2) • Complications of allogeneic HSCT: Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. (5.3) • Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. (5.4 , 8.1 , 8.3) • Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials. (5.5) 5.1 Severe and Fatal Immune-Mediated Adverse Reactions OPDIVO is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD‑1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue OPDIVO depending on severity [see Dosage and Administration (2.3) ] . In general, if OPDIVO requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below. Immune-Mediated Pneumonitis OPDIVO can cause immune-mediated pneumonitis, which is defined as requiring use of steroids and no clear alternate etiology. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation. OPDIVO as a Single Agent Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients receiving OPDIVO as a single agent, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%) adverse reactions. Pneumonitis led to permanent discontinuation of OPDIVO in 1.1% and withholding of OPDIVO in 0.8% of patients. Systemic corticosteroids were required in 100% (61/61) of patients with pneumonitis. Pneumonitis resolved in 84% of the 61 patients. Of the 15 patients in whom OPDIVO was withheld for pneumonitis, 14 reinitiated OPDIVO after symptom improvement; of these, 4 (29%) had recurrence of pneumonitis. OPDIVO with Ipilimumab OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: In NSCLC, immune-mediated pneumonitis occurred in 9% (50/576) of patients receiving OPDIVO 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4%) immune-mediated pneumonitis. Four patients (0.7%) died due to pneumonitis. Immune-mediated pneumonitis led to permanent discontinuation of OPDIVO with ipilimumab in 5% of patients and withholding of OPDIVO with ipilimumab in 3.6% of patients. Systemic corticosteroids were required in 100% of patients with pneumonitis. Pneumonitis resolved in 72% of the patients. Approximately 13% (2/16) of patients had recurrence of pneumonitis after reinitiation of OPDIVO with ipilimumab. Immune-Mediated Colitis OPDIVO can cause immune-mediated colitis, defined as requiring use of corticosteroids and no clear alternate etiology. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. OPDIVO as a Single Agent Immune-mediated colitis occurred in 2.9% (58/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (1.7%) and Grade 2 (1%) adverse reactions. Colitis led to permanent discontinuation of OPDIVO in 0.7% and withholding of OPDIVO in 0.9% of patients. Systemic corticosteroids were required in 100% (58/58) of patients with colitis. Four patients required addition of infliximab to high-dose corticosteroids. Colitis resolved in 86% of the 58 patients. Of the 18 patients in whom OPDIVO was withheld for colitis, 16 reinitiated OPDIVO after symptom improvement; of these, 12 (75%) had recurrence of colitis. OPDIVO with Ipilimumab OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Immune-mediated colitis occurred in 25% (115/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (0.4%), Grade 3 (14%), and Grade 2 (8%) adverse reactions. Colitis led to permanent discontinuation of OPDIVO with ipilimumab in 14% and withholding of OPDIVO with ipilimumab in 4.4% of patients. Systemic corticosteroids were required in 100% (115/115) of patients with colitis. Approximately 23% of patients required addition of infliximab to high-dose corticosteroids. Colitis resolved in 93% of the 115 patients. Of the 20 patients in whom OPDIVO with ipilimumab was withheld for colitis, 16 reinitiated treatment after symptom improvement; of these, 9 (56%) had recurrence of colitis. OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Immune-mediated colitis occurred in 9% (60/666) of patients with RCC or CRC receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (4.4%) and Grade 2 (3.7%) adverse reactions. Colitis led to permanent discontinuation of OPDIVO with ipilimumab in 3.2% and withholding of OPDIVO with ipilimumab in 2.7% of patients with RCC or CRC. Systemic corticosteroids were required in 100% (60/60) of patients with colitis. Approximately 23% of patients with immune-mediated colitis required addition of infliximab to high-dose corticosteroids. Colitis resolved in 95% of the 60 patients. Of the 18 patients in whom OPDIVO with ipilimumab was withheld for colitis, 16 reinitiated treatment after symptom improvement; of these, 10 (63%) had recurrence of colitis. Immune-Mediated Hepatitis and Hepatotoxicity OPDIVO can cause immune-mediated hepatitis, defined as requiring the use of corticosteroids and no clear alternate etiology. OPDIVO as a Single Agent Immune-mediated hepatitis occurred in 1.8% (35/1994) of patients receiving OPDIVO as a single agent, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%) adverse reactions. Hepatitis led to permanent discontinuation of OPDIVO in 0.7% and withholding of OPDIVO in 0.6% of patients. Systemic corticosteroids were required in 100% (35/35) of patients with hepatitis. Two patients required the addition of mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 91% of the 35 patients. Of the 12 patients in whom OPDIVO was withheld for hepatitis, 11 reinitiated OPDIVO after symptom improvement; of these, 9 (82%) had recurrence of hepatitis. OPDIVO with Ipilimumab OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Immune-mediated hepatitis occurred in 15% (70/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%) adverse reactions. Immune-mediated hepatitis led to permanent discontinuation of OPDIVO with ipilimumab in 8% or withholding of OPDIVO with ipilimumab in 3.5% of patients. Systemic corticosteroids were required in 100% (70/70) of patients with hepatitis. Approximately 9% of patients with immune-mediated hepatitis required the addition of mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 91% of the 70 patients. Of the 16 patients in whom OPDIVO with ipilimumab was withheld for hepatitis, 14 reinitiated treatment after symptom improvement; of these, 8 (57%) had recurrence of hepatitis. OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Immune-mediated hepatitis occurred in 7% (48/666) of patients with RCC or CRC receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%) adverse reactions. Immune-mediated hepatitis led to permanent discontinuation of OPDIVO with ipilimumab in 3.6% and withholding of OPDIVO with ipilimumab in 2.6% of patients with RCC or CRC. Systemic corticosteroids were required in 100% (48/48) of patients with hepatitis. Approximately 19% of patients with immune-mediated hepatitis required addition of mycophenolic acid to high-dose corticosteroids. Hepatitis resolved in 88% of the 48 patients. Of the 17 patients in whom OPDIVO with ipilimumab was withheld for hepatitis, 14 reinitiated treatment after symptom improvement; of these, 10 (71%) had recurrence of hepatitis. OPDIVO with Cabozantinib OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to OPDIVO alone. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt OPDIVO and cabozantinib and consider administering corticosteroids [see Dosage and Administration (2.3) ] . With the combination of OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients [see Adverse Reactions (6.1) ] . ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either OPDIVO (n=11) or cabozantinib (n=9) administered as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving OPDIVO, 2 patients receiving cabozantinib, and 7 patients receiving both OPDIVO and cabozantinib. Immune-Mediated Endocrinopathies Adrenal Insufficiency OPDIVO can cause primary or secondary adrenal insufficiency. For grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold OPDIVO depending on severity [see Dosage and Administration (2.3) ] . OPDIVO as a Single Agent Adrenal insufficiency occurred in 1% (20/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.4%) and Grade 2 (0.6%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO in 0.1% and withholding of OPDIVO in 0.4% of patients. Approximately 85% of patients with adrenal insufficiency received hormone replacement therapy. Systemic corticosteroids were required in 90% (18/20) of patients with adrenal insufficiency. Adrenal insufficiency resolved in 35% of the 20 patients. Of the 8 patients in whom OPDIVO was withheld for adrenal insufficiency, 4 reinitiated OPDIVO after symptom improvement and all required hormone replacement therapy for their ongoing adrenal insufficiency. OPDIVO with Ipilimumab OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Adrenal insufficiency occurred in 8% (35/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO with ipilimumab in 0.4% and withholding of OPDIVO with ipilimumab in 2% of patients. Approximately 71% (25/35) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 37% of the 35 patients. Of the 9 patients in whom OPDIVO with ipilimumab was withheld for adrenal insufficiency, 7 reinitiated treatment after symptom improvement and all required hormone replacement therapy for their ongoing adrenal insufficiency. OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Adrenal insufficiency occurred in 7% (48/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO with ipilimumab in 1.2% and withholding of OPDIVO with ipilimumab in 2.1% of patients with RCC or CRC. Approximately 94% (45/48) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 29% of the 48 patients. Of the 14 patients in whom OPDIVO with ipilimumab was withheld for adrenal insufficiency, 11 reinitiated treatment after symptom improvement; of these, all received hormone replacement therapy and 2 (18%) had recurrence of adrenal insufficiency. OPDIVO with Cabozantinib Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received OPDIVO with cabozantinib, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of OPDIVO and cabozantinib in 0.9% and withholding of OPDIVO and cabozantinib in 2.8% of patients with RCC. Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom OPDIVO with cabozantinib was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency. Hypophysitis OPDIVO can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue OPDIVO depending on severity [see Dosage and Administration (2.3) ] . OPDIVO as a Single Agent Hypophysitis occurred in 0.6% (12/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.2%) and Grade 2 (0.3%) adverse reactions. Hypophysitis led to permanent discontinuation of OPDIVO in <0.1% and withholding of OPDIVO in 0.2% of patients. Approximately 67% (8/12) of patients with hypophysitis received hormone replacement therapy, including systemic corticosteroids. Hypophysitis resolved in 42% of the 12 patients. Of the 3 patients in whom OPDIVO was withheld for hypophysitis, 2 reinitiated OPDIVO after symptom improvement; of these, none had recurrence of hypophysitis. OPDIVO with Ipilimumab OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Hypophysitis occurred in 9% (42/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (2.4%) and Grade 2 (6%) adverse reactions. Hypophysitis led to permanent discontinuation of OPDIVO with ipilimumab in 0.9% and withholding of OPDIVO with ipilimumab in 4.2% of patients. Approximately 86% of patients with hypophysitis received hormone replacement therapy. Systemic corticosteroids were required in 88% (37/42) of patients with hypophysitis. Hypophysitis resolved in 38% of the 42 patients. Of the 19 patients in whom OPDIVO with ipilimumab was withheld for hypophysitis, 9 reinitiated treatment after symptom improvement; of these, 1 (11%) had recurrence of hypophysitis. OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Hypophysitis occurred in 4.4% (29/666) of patients with RCC or CRC receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%) adverse reactions. Hypophysitis led to permanent discontinuation of OPDIVO with ipilimumab in 1.2% and withholding of OPDIVO with ipilimumab in 2.1% of patients with RCC or CRC. Approximately 72% (21/29) of patients with hypophysitis received hormone replacement therapy, including systemic corticosteroids. Hypophysitis resolved in 59% of the 29 patients. Of the 14 patients in whom OPDIVO with ipilimumab was withheld for hypophysitis, 11 reinitiated treatment after symptom improvement; of these, 2 (18%) had recurrence of hypophysitis. Thyroid Disorders OPDIVO can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement or medical management as clinically indicated. Withhold or permanently discontinue OPDIVO depending on severity [see Dosage and Administration (2.3) ] . Thyroiditis OPDIVO as a Single Agent Thyroiditis occurred in 0.6% (12/1994) of patients receiving OPDIVO as a single agent, including Grade 2 (0.2%) adverse reactions. Thyroiditis led to permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.2% of patients. Systemic corticosteroids were required in 17% (2/12) of patients with thyroiditis. Thyroiditis resolved in 58% of the 12 patients. Of the 3 patients in whom OPDIVO was withheld for thyroiditis, 1 reinitiated OPDIVO after symptom improvement without recurrence of thyroiditis. Hyperthyroidism OPDIVO as a Single Agent Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (<0.1%) and Grade 2 (1.2%) adverse reactions. Hyperthyroidism led to the permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.4% of patients. Approximately 19% of patients with hyperthyroidism received methimazole, 7% received carbimazole, and 4% received propylthiouracil. Systemic corticosteroids were required in 9% (5/54) of patients. Hyperthyroidism resolved in 76% of the 54 patients. Of the 7 patients in whom OPDIVO was withheld for hyperthyroidism, 4 reinitiated OPDIVO after symptom improvement; of these, none had recurrence of hyperthyroidism. OPDIVO with Ipilimumab OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Hyperthyroidism occurred in 9% (42/456) of patients with melanoma or HCC who received OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (0.9%) and Grade 2 (4.2%) adverse reactions. Hyperthyroidism led to the permanent discontinuation of OPDIVO with ipilimumab in no patients and withholding of OPDIVO with ipilimumab in 2.4% of patients. Approximately 26% of patients with hyperthyroidism received methimazole and 21% received carbimazole. Systemic corticosteroids were required in 17% (7/42) of patients. Hyperthyroidism resolved in 91% of the 42 patients. Of the 11 patients in whom OPDIVO with ipilimumab was withheld for hyperthyroidism, 8 reinitiated treatment after symptom improvement; of these, 1 (13%) had recurrence of hyperthyroidism. OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Hyperthyroidism occurred in 12% (80/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (0.6%) and Grade 2 (4.5%) adverse reactions. Hyperthyroidism led to permanent discontinuation of OPDIVO with ipilimumab in no patients and withholding of OPDIVO with ipilimumab in 2.3% of patients with RCC or CRC. Of the 80 patients with RCC or CRC who developed hyperthyroidism, approximately 16% received methimazole and 3% received carbimazole. Systemic corticosteroids were required in 20% (16/80) of patients with hyperthyroidism. Hyperthyroidism resolved in 85% of the 80 patients. Of the 15 patients in whom OPDIVO with ipilimumab was withheld for hyperthyroidism, 11 reinitiated treatment after symptom improvement; of these, 3 (27%) had recurrence of hyperthyroidism. Hypothyroidism OPDIVO as a Single Agent Hypothyroidism occurred in 8% (163/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.2%) and Grade 2 (4.8%) adverse reactions. Hypothyroidism led to the permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.5% of patients. Approximately 79% of patients with hypothyroidism received levothyroxine. Systemic corticosteroids were required in 3.1% (5/163) of patients with hypothyroidism. Hypothyroidism resolved in 35% of the 163 patients. Of the 9 patients in whom OPDIVO was withheld for hypothyroidism, 3 reinitiated OPDIVO after symptom improvement; of these, 1 (33%) had recurrence of hypothyroidism. OPDIVO with Ipilimumab OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Hypothyroidism occurred in 20% (91/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (0.4%) and Grade 2 (11%) adverse reactions. Hypothyroidism led to the permanent discontinuation of OPDIVO with ipilimumab in 0.9% and withholding of OPDIVO with ipilimumab in 0.9% of patients. Approximately 89% of patients with hypothyroidism received levothyroxine. Systemic corticosteroids were required in 2.2% (2/91) of patients with hypothyroidism. Hypothyroidism resolved in 41% of the 91 patients. Of the 4 patients in whom OPDIVO with ipilimumab was withheld for hypothyroidism, 2 reinitiated treatment after symptom improvement; of these, none had recurrence of hypothyroidism. OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Hypothyroidism occurred in 18% (122/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (0.6%) and Grade 2 (11%) adverse reactions. Hypothyroidism led to permanent discontinuation of OPDIVO with ipilimumab in 0.2% and withholding of OPDIVO with ipilimumab in 1.4% of patients with RCC or CRC. Of the 122 patients with RCC or CRC who developed hypothyroidism, approximately 82% received levothyroxine. Systemic corticosteroids were required in 7% (9/122) of patients with hypothyroidism. Hypothyroidism resolved in 27% of the 122 patients. Of the 9 patients in whom OPDIVO with ipilimumab was withheld for hypothyroidism, 5 reinitiated treatment after symptom improvement; of these, 1 (20%) had recurrence of hypothyroidism. Type 1 Diabetes Mellitus, which can present with Diabetic Ketoacidosis Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold OPDIVO depending on severity [see Dosage and Administration (2.3) ] . OPDIVO as a Single Agent Diabetes occurred in 0.9% (17/1994) of patients receiving OPDIVO as a single agent, including Grade 3 (0.4%) and Grade 2 (0.3%) adverse reactions, and two cases of diabetic ketoacidosis. Diabetes led to the permanent discontinuation of OPDIVO in no patients and withholding of OPDIVO in 0.1% of patients. No patients (0/17) with diabetes required systemic corticosteroids. Diabetes resolved in 29% of the 17 patients. Of the 2 patients in whom OPDIVO was withheld for diabetes, both reinitiated OPDIVO after symptom improvement; of these, neither had recurrence of diabetes. Immune-Mediated Nephritis with Renal Dysfunction OPDIVO can cause immune-mediated nephritis, which is defined as requiring use of steroids and no clear alternate etiology. OPDIVO as a Single Agent Immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients receiving OPDIVO as a single agent, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%) adverse reactions. Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of OPDIVO in 0.3% and withholding of OPDIVO in 0.4% of patients. Systemic corticosteroids were required in 100% (23/23) of patients with nephritis and renal dysfunction. Nephritis and renal dysfunction resolved in 78% of the 23 patients. Of the 7 patients in whom OPDIVO was withheld for nephritis or renal dysfunction, 7 reinitiated OPDIVO after symptom improvement; of these, 1 (14%) had recurrence of nephritis or renal dysfunction. Immune-Mediated Dermatologic Adverse Reactions OPDIVO can cause immune-mediated rash or dermatitis, defined as requiring the use of steroids and no clear alternate etiology. Exfoliative dermatitis, including Stevens-Johnson Syndrome, toxic epidermal necrolysis (TEN), and DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue OPDIVO depending on severity [see Dosage and Administration (2.3) ] . OPDIVO as a Single Agent Immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%) adverse reactions. Immune-mediated rash led to permanent discontinuation of OPDIVO in 0.3% and withholding of OPDIVO in 0.5% of patients. Systemic corticosteroids were required in 100% (171/171) of patients with immune-mediated rash. Rash resolved in 72% of the 171 patients. Of the 10 patients in whom OPDIVO was withheld for immune-mediated rash, 9 reinitiated OPDIVO after symptom improvement; of these, 3 (33%) had recurrence of immune-mediated rash. OPDIVO with Ipilimumab OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg: Immune-mediated rash occurred in 28% (127/456) of patients with melanoma or HCC receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, including Grade 3 (4.8%) and Grade 2 (10%) adverse reactions. Immune-mediated rash led to permanent discontinuation of OPDIVO with ipilimumab in 0.4% and withholding of OPDIVO with ipilimumab in 3.9% of patients. Systemic corticosteroids were required in 100% (127/127) of patients with immune-mediated rash. Rash resolved in 84% of the 127 patients. Of the 18 patients in whom OPDIVO with ipilimumab was withheld for immune-mediated rash, 15 reinitiated treatment after symptom improvement; of these, 8 (53%) had recurrence of immune-mediated rash. OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Immune-mediated rash occurred in 16% (108/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (3.5%) and Grade 2 (4.2%) adverse reactions. Immune-mediated rash led to permanent discontinuation of OPDIVO with ipilimumab in 0.5% of patients and withholding of OPDIVO with ipilimumab in 2.0% of patients with RCC or CRC. Systemic corticosteroids were required in 100% (108/108) of patients with immune-mediated rash. Rash resolved in 75% of the 108 patients. Of the 13 patients in whom OPDIVO with ipilimumab was withheld for immune-mediated rash, 11 reinitiated treatment after symptom improvement; of these, 5 (46%) had recurrence of immune-mediated rash. Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO or OPDIVO in combination with ipilimumab, or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatic Endocrine: Hypoparathyroidism Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection 5.2 Infusion-Related Reactions OPDIVO can cause severe infusion-related reactions, which have been reported in <1% of patients in clinical trials. Discontinue OPDIVO in patients with severe or life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion-related reactions [see Dosage and Administration (2.3) ] . OPDIVO as a Single Agent In patients who received OPDIVO as a 60-minute intravenous infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a trial assessing the pharmacokinetics and safety of a more rapid infusion, in which patients received OPDIVO as a 60-minute intravenous infusion or a 30-minute intravenous infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation, or withholding of OPDIVO. OPDIVO with Ipilimumab OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg Infusion-related reactions occurred in 2.5% (10/407) of patients with melanoma and in 8% (4/49) of patients with HCC who received OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks. OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg Infusion-related reactions occurred in 5.1% (28/547) of patients with RCC and 4.2% (5/119) of patients with CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, respectively. Infusion-related reactions occurred in 12% (37/300) of patients with malignant pleural mesothelioma who received OPDIVO 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks. 5.3 Complications of Allogeneic Hematopoietic Stem Cell Transplantation Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1 receptor blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause) [see Adverse Reactions (6.1) ] . These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1 receptor blocking antibody prior to or after an allogeneic HSCT. 5.4 Embryo-Fetal Toxicity Based on its mechanism of action and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for 5 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] . 5.5 Increased Mortality in Patients with Multiple Myeloma when OPDIVO Is Added to a Thalidomide Analogue and Dexamethasone In randomized clinical trials in patients with multiple myeloma, the addition of a PD-1 blocking antibody, including OPDIVO, to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling. • Severe and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) ] • Infusion-Related Reactions [see Warnings and Precautions (5.2) ] • Complications of Allogeneic HSCT [see Warnings and Precautions (5.3) ] Most common adverse reactions (incidence ≥20%) in patients were: • As a single agent: fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia, headache, abdominal pain, vomiting, and urinary tract infection. (6.1) • In combination with ipilimumab: fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, constipation, decreased weight, and dizziness. (6.1) • In combination with platinum-doublet chemotherapy: nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and peripheral neuropathy. (6.1) • In combination with ipilimumab and platinum-doublet chemotherapy: fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus. (6.1) • In combination with cabozantinib: diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection. (6.1) • In combination with fluoropyrimidine- and platinum-containing chemotherapy: nausea, peripheral neuropathy, decreased appetite, fatigue, constipation, stomatitis, diarrhea, vomiting, abdominal pain, and musculoskeletal pain. (6.1) Most common adverse reactions (incidence ≥30%) in patients were: • In combination with AVD: nausea, neutropenia, fatigue, anemia, constipation, leukopenia, musculoskeletal pain, peripheral neuropathy, transaminases increase, vomiting, and stomatitis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in WARNINGS AND PRECAUTIONS reflect exposure to OPDIVO as a single agent in 1994 patients enrolled in CHECKMATE-037, CHECKMATE-017, CHECKMATE-057, CHECKMATE-066, CHECKMATE-025, CHECKMATE-067, CHECKMATE-205, CHECKMATE-039 or a single-arm trial in NSCLC (n=117); OPDIVO 1 mg/kg with ipilimumab 3 mg/kg in patients enrolled in CHECKMATE-067 (n=313), CHECKMATE-040 (n=49), or another randomized trial (n=94); OPDIVO 3 mg/kg administered with ipilimumab 1 mg/kg (n=666) in patients enrolled in CHECKMATE-214 or CHECKMATE-142; OPDIVO 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks in patients enrolled in CHECKMATE-227 (n=576) or CHECKMATE-743 (n=300); OPDIVO 360 mg with ipilimumab 1 mg/kg and 2 cycles of platinum-doublet chemotherapy in CHECKMATE-9LA (n=361); OPDIVO 240 mg with cabozantinib 40 mg in patients enrolled in CHECKMATE-9ER (n=320); and OPDIVO 240 mg or 3 mg/kg with AVD in patients enrolled in CA209-8UT (SWOG 1826) (n=490). Unresectable or Metastatic Melanoma Previously Treated Metastatic Melanoma The safety of OPDIVO was evaluated in CHECKMATE-037, a randomized, open-label trial in 370 patients with unresectable or metastatic melanoma [see Clinical Studies (14.1) ] . Patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumab-related Grade 4 adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, and a history of HIV. Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102): dacarbazine 1000 mg/m 2 intravenously every 3 weeks or carboplatin AUC 6 mg/mL/min and paclitaxel 175 mg/m 2 intravenously every 3 weeks. The median duration of exposure was 5.3 months (range: 1 day to 13.8+ months) in OPDIVO-treated patients and was 2 months (range: 1 day to 9.6+ months) in chemotherapy-treated patients. In this ongoing trial, 24% of patients received OPDIVO for >6 months and 3% of patients received OPDIVO for >1 year. The population characteristics in the OPDIVO group and the chemotherapy group were similar: 66% male, median age 59.5 years, 98% White, baseline Eastern Cooperative Oncology Group (ECOG) performance status 0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more patients in the OPDIVO group with elevated lactate dehydrogenase (LDH) at baseline (51% vs. 38%). Serious adverse reactions occurred in 41% of patients receiving OPDIVO. OPDIVO was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving OPDIVO had a dose interruption for an adverse reaction. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. The most common adverse reaction (reported in ≥20% of patients) was rash. Tables 5 and 6 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-037. Table 5: Adverse Reactions Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-037 Toxicity was graded per NCI CTCAE v4. a Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, and acneiform dermatitis. b Includes rhinitis, pharyngitis, and nasopharyngitis. Adverse Reaction OPDIVO (n=268) Chemotherapy (n=102) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Skin and Subcutaneous Tissue Rash a 21 0.4 7 0 Pruritus 19 0 3.9 0 Respiratory, Thoracic and Mediastinal Cough 17 0 6 0 Infections Upper respiratory tract infection b 11 0 2 0 General Peripheral edema 10 0 5 0 Clinically important adverse reactions in <10% of patients who received OPDIVO were: Cardiac Disorders: ventricular arrhythmia Eye Disorders: iridocyclitis General Disorders and Administration Site Conditions: infusion-related reactions Investigations: increased amylase, increased lipase Nervous System Disorders: dizziness, peripheral and sensory neuropathy Skin and Subcutaneous Tissue Disorders: exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis Table 6: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Chemotherapy Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-037 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 252 to 256 patients) and chemotherapy group (range: 94 to 96 patients). Laboratory Abnormality OPDIVO Chemotherapy All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Increased AST 28 2.4 12 1 Hyponatremia 25 5 18 1.1 Increased alkaline phosphatase 22 2.4 13 1.1 Increased ALT 16 1.6 5 0 Hyperkalemia 15 2 6 0 Previously Untreated Metastatic Melanoma CHECKMATE-066 The safety of OPDIVO was also evaluated in CHECKMATE-066, a randomized, double-blind, active-controlled trial in 411 previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma [see Clinical Studies (14.1) ] . The trial excluded patients with autoimmune disease and patients requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications. Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=206) or dacarbazine 1000 mg/m 2 intravenously every 3 weeks (n=205). The median duration of exposure was 6.5 months (range: 1 day to 16.6 months) in OPDIVO-treated patients. In this trial, 47% of patients received OPDIVO for >6 months and 12% of patients received OPDIVO for >1 year. The trial population characteristics in the OPDIVO group and dacarbazine group: 59% male, median age 65 years, 99.5% White, 61% with M1c stage disease, 74% with cutaneous melanoma, 11% with mucosal melanoma, 4% with brain metastasis, and 37% with elevated LDH at baseline. There were more patients in the OPDIVO group with ECOG performance status 0 (71% vs. 59%). Serious adverse reactions occurred in 36% of patients receiving OPDIVO. Adverse reactions led to permanent discontinuation of OPDIVO in 7% of patients and dose interruption in 26% of patients; no single type of adverse reaction accounted for the majority of OPDIVO discontinuations. Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were increased gamma-glutamyl transferase (3.9%) and diarrhea (3.4%). The most common adverse reactions (reported in ≥20% of patients and at a higher incidence than in the dacarbazine arm) were fatigue, musculoskeletal pain, rash, and pruritus. Tables 7 and 8 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-066. Table 7: Adverse Reactions Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-066 Toxicity was graded per NCI CTCAE v4. a Includes periorbital edema, face edema, generalized edema, gravitational edema, localized edema, peripheral edema, pulmonary edema, and lymphedema. b Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, pain in jaw, and spinal pain. c Includes maculopapular rash, erythematous rash, pruritic rash, follicular rash, macular rash, papular rash, pustular rash, vesicular rash, dermatitis, allergic dermatitis, exfoliative dermatitis, acneiform dermatitis, drug eruption, and skin reaction. d Includes rhinitis, viral rhinitis, pharyngitis, and nasopharyngitis. Adverse Reaction OPDIVO (n=206) Dacarbazine (n=205) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue 49 1.9 39 3.4 Edema a 12 1.5 4.9 0 Musculoskeletal and Connective Tissue Musculoskeletal pain b 32 2.9 25 2.4 Skin and Subcutaneous Tissue Rash c 28 1.5 12 0 Pruritus 23 0.5 12 0 Vitiligo 11 0 0.5 0 Erythema 10 0 2.9 0 Infections Upper respiratory tract infection d 17 0 6 0 Clinically important adverse reactions in <10% of patients who received OPDIVO were: Nervous System Disorders: peripheral neuropathy Table 8: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-066 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 194 to 197 patients) and dacarbazine group (range: 186 to 193 patients). Laboratory Abnormality OPDIVO Dacarbazine All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Increased ALT 25 3 19 0.5 Increased AST 24 3.6 19 0.5 Increased alkaline phosphatase 21 2.6 14 1.6 Increased bilirubin 13 3.1 6 0 CHECKMATE-067 The safety of OPDIVO, administered with ipilimumab or as a single agent, was evaluated in CHECKMATE-067, a randomized (1:1:1), double-blind trial in 937 patients with previously untreated, unresectable or metastatic melanoma [see Clinical Studies (14.1) ] . The trial excluded patients with autoimmune disease, a medical condition requiring systemic treatment with corticosteroids (more than 10 mg daily prednisone equivalent) or other immunosuppressive medication within 14 days of the start of study therapy, a positive test result for hepatitis B or C, or a history of HIV. Patients were randomized to receive: • OPDIVO 1 mg/kg over 60 minutes with ipilimumab 3 mg/kg by intravenous infusion every 3 weeks for 4 doses followed by OPDIVO as a single agent at a dose of 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (OPDIVO and ipilimumab arm; n=313), or • OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (OPDIVO arm; n=313), or • Ipilimumab 3 mg/kg by intravenous infusion every 3 weeks for up to 4 doses (ipilimumab arm; n=311). The median duration of exposure to OPDIVO was 2.8 months (range: 1 day to 36.4 months) for the OPDIVO and ipilimumab arm and 6.6 months (range: 1 day to 36.0 months) for the OPDIVO arm. In the OPDIVO and ipilimumab arm, 39% were exposed to OPDIVO for ≥6 months and 30% exposed for >1 year. In the OPDIVO arm, 53% were exposed for ≥6 months and 40% for >1 year. The population characteristics were: 65% male, median age 61 years, 97% White, baseline ECOG performance status 0 (73%) or 1 (27%), 93% with American Joint Committee on Cancer (AJCC) Stage IV disease, 58% with M1c stage disease; 36% with elevated LDH at baseline, 4% with a history of brain metastasis, and 22% had received adjuvant therapy. Serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO and ipilimumab arm relative to the OPDIVO arm. The most frequent (≥10%) serious adverse reactions in the OPDIVO and ipilimumab arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1%). The most frequent adverse reactions leading to discontinuation of both drugs in the OPDIVO and ipilimumab arm and of OPDIVO in the OPDIVO arm, respectively, were colitis (10% and 0.6%), diarrhea (8% and 2.2%), increased ALT (4.8% and 1%), increased AST (4.5% and 0.6%), and pneumonitis (1.9% and 0.3%). The most common (≥20%) adverse reactions in the OPDIVO and ipilimumab arm were fatigue, diarrhea, rash, nausea, pyrexia, pruritus, musculoskeletal pain, vomiting, decreased appetite, cough, headache, dyspnea, upper respiratory tract infection, arthralgia, and increased transaminases. The most common (≥20%) adverse reactions in the OPDIVO arm were fatigue, rash, musculoskeletal pain, diarrhea, nausea, cough, pruritus, upper respiratory tract infection, decreased appetite, headache, constipation, arthralgia, and vomiting. Tables 9 and 10 summarize the incidence of adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-067. Table 9: Adverse Reactions Occurring in ≥10% of Patients on the OPDIVO and Ipilimumab Arm or the OPDIVO Arm and at a Higher Incidence than in the Ipilimumab Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-067 Toxicity was graded per NCI CTCAE v4. a Includes asthenia and fatigue. b Includes pustular rash, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, exfoliative dermatitis, psoriasiform dermatitis, drug eruption, exfoliative rash, erythematous rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, papulosquamous rash, and pruritic rash. c Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain. d Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis. e Includes hypertension and blood pressure increased. Adverse Reaction OPDIVO and Ipilimumab (n=313) OPDIVO (n=313) Ipilimumab (n=311) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue a 62 7 59 1.6 51 4.2 Pyrexia 40 1.6 16 0 18 0.6 Gastrointestinal Diarrhea 54 11 36 5 47 7 Nausea 44 3.8 30 0.6 31 1.9 Vomiting 31 3.8 20 1 17 1.6 Skin and Subcutaneous Tissue Rash b 53 6 40 1.9 42 3.5 Vitiligo 9 0 10 0.3 5 0 Musculoskeletal and Connective Tissue Musculoskeletal pain c 32 2.6 42 3.8 36 1.9 Arthralgia 21 0.3 21 1 16 0.3 Metabolism and Nutrition Decreased appetite 29 1.9 22 0 24 1.3 Respiratory, Thoracic and Mediastinal Cough/productive cough 27 0.3 28 0.6 22 0 Dyspnea/exertional dyspnea 24 2.9 18 1.3 17 0.6 Infections Upper respiratory tract infection d 23 0 22 0.3 17 0 Endocrine Hypothyroidism 19 0.6 11 0 5 0 Hyperthyroidism 11 1.3 6 0 1 0 Investigations Decreased weight 12 0 7 0 7 0.3 Vascular Hypertension e 7 2.2 11 5 9 2.3 Clinically important adverse reactions in <10% of patients who received OPDIVO with ipilimumab or OPDIVO as a single agent were: Gastrointestinal Disorders: stomatitis, intestinal perforation Skin and Subcutaneous Tissue Disorders: vitiligo Musculoskeletal and Connective Tissue Disorders: myopathy, Sjogren’s syndrome, spondyloarthropathy, myositis (including polymyositis) Nervous System Disorders: neuritis, peroneal nerve palsy Table 10: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥20% of Patients Treated with OPDIVO with Ipilimumab or Single-Agent OPDIVO and at a Higher Incidence than in the Ipilimumab Arm (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-067 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and ipilimumab (range: 75 to 297); OPDIVO (range: 81 to 306); ipilimumab (range: 61 to 301). Laboratory Abnormality OPDIVO and Ipilimumab OPDIVO Ipilimumab All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Chemistry Increased ALT 55 16 25 3 29 2.7 Hyperglycemia 53 5.3 46 7 26 0 Increased AST 52 13 29 3.7 29 1.7 Hyponatremia 45 10 22 3.3 26 7 Increased lipase 43 22 32 12 24 7 Increased alkaline phosphatase 41 6 27 2 23 2 Hypocalcemia 31 1.1 15 0.7 20 0.7 Increased amylase 27 10 19 2.7 15 1.6 Increased creatinine 26 2.7 19 0.7 17 1.3 Hematology Anemia 52 2.7 41 2.6 41 6 Lymphopenia 39 5 41 4.9 29 4 Adjuvant Treatment of Melanoma CHECKMATE-76K The safety of OPDIVO as a single agent was evaluated in CHECKMATE-76K, a randomized (2:1), double-blind trial in 788 patients with completely resected Stage IIB/C melanoma who received OPDIVO 480 mg by intravenous infusion over 30 minutes every 4 weeks (n=524) or placebo by intravenous infusion over 30 minutes every 4 weeks (n=264) for up to 1 year [see Clinical Studies (14.2) ] . The median duration of exposure was 11 months in patients treated with OPDIVO and 11 months in patients treated with placebo. Serious adverse reactions occurred in 18% of patients treated with OPDIVO. A fatal adverse reaction occurred in 1 (0.2%) patient (heart failure and acute kidney injury). Permanent discontinuation of OPDIVO due to an adverse reaction occurred in 17% of patients. Adverse reactions which resulted in permanent discontinuation of OPDIVO in >1% of patients included diarrhea (1.1%), arthralgia (1.7%), and rash (1.7%). Dosage interruptions of OPDIVO due to an adverse reaction occurred in 25% of patients. Adverse reactions which required dosage interruption in >1% of patients included COVID-19 infection, infusion related reaction, diarrhea, arthralgia, and increased ALT. The most common adverse reactions (reported in ≥20% of patients) were fatigue, musculoskeletal pain, rash, diarrhea, and pruritus. Tables 11 and 12 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-76K. Table 11: Adverse Reactions Occurring in ≥10% of Patients Treated with OPDIVO - CHECKMATE-76K Toxicity was graded per NCI CTCAE v5. a Includes asthenia. b Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, spinal pain, pain in extremity. c Includes dermatitis, dermatitis acneiform, dyshidrotic eczema, eczema, eczema asteatotic, eyelid rash, genital rash, pemphigoid, penile rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, skin exfoliation, toxic skin eruption. d Includes autoimmune colitis, colitis, diarrhea, enteritis, enterocolitis. e Includes autoimmune hypothyroidism, blood thyroid stimulating hormone increased. f Includes cluster headache, migraine. Adverse Reaction OPDIVO (n=524) Placebo (n=264) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue a 36 0.4 34 0.4 Musculoskeletal and connective tissue Musculoskeletal pain b 30 0.4 26 0.4 Skin and Subcutaneous Tissue Rash c 28 1.1 15 0.4 Pruritus 20 0.2 11 0 Gastrointestinal Diarrhea d 23 1.3 16 0 Nausea 14 0 11 0 Endocrine Hypothyroidism e 14 0 2.3 0 Nervous system Headache f 12 0.2 14 0.8 Table 12: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥10% of OPDIVO-Treated Patients - CHECKMATE-76K a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 262 to 513 patients) and placebo group (range: 138 to 261 patients). Laboratory Abnormality OPDIVO (n=524) Placebo (n=264) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Hematology Anemia 19 0 14 0 Lymphopenia 17 1.1 17 1.7 Neutropenia 10 0 10 0.4 Chemistry AST increased 25 2.2 16 0.4 Lipase increased 22 2.9 21 2.3 ALT increased 20 2.1 15 0.4 Amylase increased 17 0.4 9 0 Creatinine increased 15 0.4 13 0 Sodium decreased 13 0.6 11 0.4 Potassium increased 13 1 15 1.1 CHECKMATE-238 The safety of OPDIVO as a single agent was evaluated in CHECKMATE-238, a randomized (1:1), double-blind trial in 905 patients with completely resected Stage IIIB/C or Stage IV melanoma received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=452) or ipilimumab 10 mg/kg by intravenous infusion every 3 weeks for 4 doses then every 12 weeks beginning at Week 24 for up to 1 year (n=453) [see Clinical Studies (14.2) ] . The median duration of exposure was 11.5 months in OPDIVO-treated patients and was 2.7 months in ipilimumab-treated patients. In this ongoing trial, 74% of patients received OPDIVO for >6 months. Serious adverse reactions occurred in 18% of OPDIVO-treated patients. Study therapy was discontinued for adverse reactions in 9% of OPDIVO-treated patients and 42% of ipilimumab-treated patients. Twenty-eight percent of OPDIVO-treated patients had at least one omitted dose for an adverse reaction. Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. The most common adverse reactions (at least 20%) were fatigue, diarrhea, rash, musculoskeletal pain, pruritus, headache, nausea, upper respiratory infection, and abdominal pain. The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). Tables 13 and 14 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-238. Table 13: Adverse Reactions Occurring in ≥10% of OPDIVO-Treated Patients - CHECKMATE-238 Toxicity was graded per NCI CTCAE v4. a Includes asthenia. b Includes abdominal discomfort, lower abdominal pain, upper abdominal pain, and abdominal tenderness. c Includes dermatitis described as acneiform, allergic, bullous, or exfoliative and rash described as generalized, erythematous, macular, papular, maculopapular, pruritic, pustular, vesicular, or butterfly, and drug eruption. d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, spinal pain, and pain in extremity. e Includes postural dizziness and vertigo. f Includes upper respiratory tract infection including viral respiratory tract infection, lower respiratory tract infection, rhinitis, pharyngitis, and nasopharyngitis. g Includes secondary hypothyroidism and autoimmune hypothyroidism. Adverse Reaction OPDIVO (n=452) Ipilimumab 10 mg/kg (n=453) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue a 57 0.9 55 2.4 Gastrointestinal Diarrhea 37 2.4 55 11 Nausea 23 0.2 28 0 Abdominal pain b 21 0.2 23 0.9 Constipation 10 0 9 0 Skin and Subcutaneous Tissue Rash c 35 1.1 47 5.3 Pruritus 28 0 37 1.1 Musculoskeletal and Connective Tissue Musculoskeletal pain d 32 0.4 27 0.4 Arthralgia 19 0.4 13 0.4 Nervous System Headache 23 0.4 31 2.0 Dizziness e 11 0 8 0 Infections Upper respiratory tract infection f 22 0 15 0.2 Respiratory, Thoracic and Mediastinal Cough/productive cough 19 0 19 0 Dyspnea/exertional dyspnea 10 0.4 10 0.2 Endocrine Hypothyroidism g 12 0.2 7.5 0.4 Table 14: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥10% of OPDIVO-Treated Patients - CHECKMATE-238 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 400 to 447 patients) and ipilimumab 10 mg/kg group (range: 392 to 443 patients). Laboratory Abnormality OPDIVO Ipilimumab 10 mg/kg All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Hematology Lymphopenia 27 0.4 12 0.9 Anemia 26 0 34 0.5 Leukopenia 14 0 2.7 0.2 Neutropenia 13 0 6 0.5 Chemistry Increased Lipase 25 7 23 9 Increased ALT 25 1.8 40 12 Increased AST 24 1.3 33 9 Increased Amylase 17 3.3 13 3.1 Hyponatremia 16 1.1 22 3.2 Hyperkalemia 12 0.2 9 0.5 Increased Creatinine 12 0 13 0 Hypocalcemia 10 0.7 16 0.5 Neoadjuvant Treatment of Resectable (Tumors ≥4 cm or Node Positive) Non-Small Cell Lung Cancer The safety of OPDIVO in combination with platinum-doublet chemotherapy was evaluated in CHECKMATE-816, a randomized, open-label, multicenter trial in patients with resectable NSCLC [see Clinical Studies (14.3) ] . Patients received either OPDIVO 360 mg administered in combination with platinum-doublet chemotherapy administered every 3 weeks for 3 cycles; or platinum-doublet chemotherapy administered every 3 weeks for 3 cycles. The median age of patients who received OPDIVO in combination with platinum-doublet chemotherapy or platinum-doublet chemotherapy was 65 years (range: 34 – 84); 72% male; 47% White, 50% Asian, and 2% Black/African American. Serious adverse reactions occurred in 30% of patients who were treated with OPDIVO in combination with platinum-doublet chemotherapy. Serious adverse reactions in >2% included pneumonia and vomiting. No fatal adverse reactions occurred in patients who received OPDIVO in combination with platinum-doublet chemotherapy. Study therapy with OPDIVO in combination with platinum-doublet chemotherapy was permanently discontinued for adverse reactions in 10% of patients and 30% had at least one treatment withheld for an adverse reaction. The most common adverse reactions (≥1%) resulting in permanent discontinuation of OPDIVO in combination with platinum-doublet chemotherapy were anaphylactic reaction (1.7%), acute kidney injury (1.1%), rash (1.1%), and fatigue (1.1%). The most common (>20%) adverse reactions were nausea, constipation, fatigue, decreased appetite, and rash. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were neutropenia, hyperglycemia, leukopenia, lymphopenia, increased amylase, anemia, thrombocytopenia, and hyponatremia. Tables 15 and 16 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-816. Table 15: Adverse Reactions in >10% of Patients with Early-Stage NSCLC Receiving Neoadjuvant OPDIVO and Platinum-Doublet Chemotherapy in CHECKMATE-816 Toxicity was graded per NCI CTCAE v4. a Includes fatigue and asthenia. b Includes rash, dermatitis, acneiform dermatitis, atopic dermatitis, bullous dermatitis, drug eruption, maculopapular rash, and pruritic rash. c Includes peripheral neuropathy, dysesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensory neuropathy. Adverse Reaction OPDIVO and Platinum-Doublet Chemotherapy (n=176) Platinum-Doublet Chemotherapy (n=176) All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) Gastrointestinal Nausea 38 0.6 45 1.1 Constipation 34 0 32 1.1 Vomiting 11 1.1 13 0.6 General Fatigue a 26 2.3 23 1.1 Malaise 15 0.6 14 0.6 Metabolism and Nutrition Decreased appetite 20 1.1 23 2.3 Skin and Subcutaneous Tissue Rash b 20 2.3 7 0 Alopecia 11 0 15 0 Nervous System Peripheral neuropathy c 13 0 6 0 Table 16: Select Laboratory Values Worsening from Baseline a Occurring in >20% of Patients with Early-Stage NSCLC Receiving Neoadjuvant OPDIVO and Platinum-Doublet Chemotherapy in CHECKMATE-816 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and platinum-doublet chemotherapy group (range: 73 to 171 patients) and platinum-doublet chemotherapy group (range: 68 to 171 patients). Laboratory Abnormality OPDIVO and Platinum-Doublet Chemotherapy a Platinum-Doublet Chemotherapy a All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) Hematology Anemia 63 3.5 70 6 Neutropenia 58 22 58 27 Leukopenia 53 5 51 11 Lymphopenia 38 4.7 31 1.8 Thrombocytopenia 24 2.9 22 3 Chemistry Hyperglycemia 37 6 35 2.9 Hypomagnesemia 25 1.2 29 1.2 Hyponatremia 25 2.4 28 1.8 Increased amylase 23 3.6 13 1.8 Increased ALT 23 0 20 1.2 Neoadjuvant and Adjuvant Treatment of Resectable Non-Small Cell Lung Cancer The safety of OPDIVO in combination with neoadjuvant platinum-doublet chemotherapy followed by surgery and continued adjuvant treatment with OPDIVO as a single agent after surgery was evaluated in CHECKMATE-77T, a randomized, double-blind, multicenter trial in patients with previously untreated resectable Stage IIA (>4 cm) to IIIB (T3N2 or T4N2) NSCLC (per the AJCC Cancer Staging Manual 8th Edition) [see Clinical Studies (14.4) ] . Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. The median duration of exposure to OPDIVO was 10.3 months (range: 1 day to 22.3 months). The study population characteristics were: median age 66 years (range: 35 - 86); 71% male; 72% White, 25% Asian, 1.7% Black/African American, and 1.5% other race; and 6% Hispanic or Latino. Adverse reactions occurring in patients with resectable NSCLC receiving OPDIVO in combination with platinum-doublet chemotherapy, given as neoadjuvant treatment and followed as a single agent adjuvant treatment after surgery, were generally similar to those occurring in patients in other clinical trials across tumor types receiving OPDIVO in combination with chemotherapy. Neoadjuvant Phase of CHECKMATE-77T A total of 228 patients received at least 1 dose of OPDIVO in combination with platinum-doublet chemotherapy as neoadjuvant treatment and 230 patients received at least 1 dose of placebo in combination with platinum-doublet chemotherapy as neoadjuvant treatment. Serious adverse reactions occurred in 21% of patients who received OPDIVO in combination with platinum-doublet chemotherapy as neoadjuvant treatment; the most frequent (≥2%) serious adverse reactions was pneumonia. Fatal adverse reactions occurred in 2.2% of patients, due to cerebrovascular accident, COVID-19 infection, hemoptysis, pneumonia, and pneumonitis (0.4% each). Permanent discontinuation of any study drug due to an adverse reaction occurred in 13% of patients who received OPDIVO in combination with platinum-doublet chemotherapy as neoadjuvant treatment; the most frequent (≥1%) adverse reaction that led to permanent discontinuation of any study drug was peripheral sensory neuropathy (2.2%). Of the 228 OPDIVO-treated patients and 230 placebo-treated patients who received neoadjuvant treatment, 5.3% (n=12) and 3.5% (n=8), respectively, did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery in OPDIVO-treated patients were cerebrovascular accident, pneumonia, and colitis/diarrhea (2 patients each) and acute coronary syndrome, myocarditis, hemoptysis, pneumonitis, COVID-19, and myositis (1 patient each). Of the 178 OPDIVO-treated patients who received surgery, 4.5% (n=8) experienced delay of surgery (surgery more than 6 weeks from last neoadjuvant treatment) due to adverse reactions. Of the 178 placebo-treated patients who received surgery, 3.9% (n=7) experienced delay of surgery due to adverse reactions. Of the 178 OPDIVO-treated patients who received surgery, 7% (n=13) did not receive adjuvant treatment due to adverse reactions. Of the 178 placebo-treated patients who received surgery, 2.8% (n=5) did not receive adjuvant treatment due to adverse reactions. Adjuvant Phase of CHECKMATE-77T A total of 142 patients in the OPDIVO arm and 152 patients in the placebo arm received at least 1 dose of adjuvant treatment. Of the patients who received single agent OPDIVO as adjuvant treatment, 22% experienced serious adverse reactions; the most frequent serious adverse reaction was pneumonitis/ILD (2.8%). One fatal adverse reaction due to COVID-19 occurred. Permanent discontinuation of adjuvant OPDIVO due to an adverse reaction occurred in 14% of patients; the most frequent (≥1%) adverse reactions that led to permanent discontinuation of adjuvant OPDIVO were pneumonitis (4.2%) and diarrhea (1.4%). Metastatic Non-Small Cell Lung Cancer First-line Treatment of Metastatic NSCLC: In Combination with Ipilimumab The safety of OPDIVO in combination with ipilimumab was evaluated in CHECKMATE-227, a randomized, multicenter, multi-cohort, open-label trial in patients with previously untreated metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations [see Clinical Studies (14.5) ] . The trial excluded patients with untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients received OPDIVO 3 mg/kg by intravenous infusion over 30 minutes every 2 weeks and ipilimumab 1 mg/kg by intravenous infusion over 30 minutes every 6 weeks or platinum-doublet chemotherapy every 3 weeks for 4 cycles. The median duration of therapy in OPDIVO and ipilimumab-treated patients was 4.2 months (range: 1 day to 25.5 months): 39% of patients received OPDIVO and ipilimumab for >6 months and 23% of patients received OPDIVO and ipilimumab for >1 year. The population characteristics were: median age 64 years (range: 26 to 87); 48% were ≥65 years of age, 76% White, and 67% male. Baseline ECOG performance status was 0 (35%) or 1 (65%), 85% were former/current smokers, 11% had brain metastases, 28% had squamous histology and 72% had non-squamous histology. Serious adverse reactions occurred in 58% of patients. OPDIVO and ipilimumab were discontinued for adverse reactions in 24% of patients and 53% had at least one dose withheld for an adverse reaction. The most frequent (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. The most common (≥20%) adverse reactions were fatigue, rash, decreased appetite, musculoskeletal pain, diarrhea/colitis, dyspnea, cough, hepatitis, nausea, and pruritus. Tables 17 and 18 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-227. Table 17: Adverse Reactions in ≥10% of Patients Receiving OPDIVO and Ipilimumab - CHECKMATE-227 a Includes fatigue and asthenia. b Includes eyelid edema, face edema, generalized edema, localized edema, edema, edema peripheral, and periorbital edema. c Includes autoimmune dermatitis, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis atopic, dermatitis bullous, dermatitis contact, dermatitis exfoliative, dermatitis psoriasiform, granulomatous dermatitis, rash generalized, drug eruption, dyshidrotic eczema, eczema, exfoliative rash, nodular rash, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, toxic skin eruption. d Includes pruritus and pruritus generalized. e Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, and pain in extremity. f Includes colitis, colitis microscopic, colitis ulcerative, diarrhea, enteritis infectious, enterocolitis, enterocolitis infectious, and enterocolitis viral. g Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. h Includes dyspnea and dyspnea exertional. i Includes cough and productive cough. j Includes alanine aminotransferase increased, aspartate aminotransferase increased, autoimmune hepatitis, blood bilirubin increased, hepatic enzyme increased, hepatic failure, hepatic function abnormal, hepatitis, hepatitis E, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, liver function test abnormal, liver function test increased, transaminases increased. k Includes autoimmune thyroiditis, blood thyroid stimulating hormone increased, hypothyroidism, primary hypothyroidism, thyroiditis, and tri-iodothyronine free decreased. l Contains blood thyroid stimulating hormone decreased, hyperthyroidism, and tri-iodothyronine free increased. m Includes lower respiratory tract infection, lower respiratory tract infection bacterial, lung infection, pneumonia, pneumonia adenoviral, pneumonia aspiration, pneumonia bacterial, pneumonia klebsiella, pneumonia influenzal, pneumonia viral, atypical pneumonia, organizing pneumonia. Adverse Reaction OPDIVO and Ipilimumab (n=576) Platinum-Doublet Chemotherapy (n=570) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue a 44 6 42 4.4 Pyrexia 18 0.5 11 0.4 Edema b 14 0.2 12 0.5 Skin and Subcutaneous Tissue Rash c 34 4.7 10 0.4 Pruritus d 21 0.5 3.3 0 Metabolism and Nutrition Decreased appetite 31 2.3 26 1.4 Musculoskeletal and Connective Tissue Musculoskeletal pain e 27 1.9 16 0.7 Arthralgia 13 0.9 2.5 0.2 Gastrointestinal Diarrhea/colitis f 26 3.6 16 0.9 Nausea 21 1 42 2.5 Constipation 18 0.3 27 0.5 Vomiting 13 1 18 2.3 Abdominal pain g 10 0.2 9 0.7 Respiratory, Thoracic, and Mediastinal Dyspnea h 26 4.3 16 2.1 Cough i 23 0.2 13 0 Hepatobiliary Hepatitis j 21 9 10 1.2 Endocrine Hypothyroidism k 16 0.5 1.2 0 Hyperthyroidism l 10 0 0.5 0 Infections and Infestations Pneumonia m 13 7 8 4 Nervous System Headache 11 0.5 6 0 Other clinically important adverse reactions in CHECKMATE-227 were: Skin and Subcutaneous Tissue: urticaria, alopecia, erythema multiforme, vitiligo Gastrointestinal: stomatitis, pancreatitis, gastritis Musculoskeletal and Connective Tissue: arthritis, polymyalgia rheumatica, rhabdomyolysis Nervous System: peripheral neuropathy, autoimmune encephalitis Blood and Lymphatic System: eosinophilia Eye Disorders: blurred vision, uveitis Cardiac: atrial fibrillation, myocarditis Table 18: Laboratory Values Worsening from Baseline a Occurring in ≥20% of Patients on OPDIVO and Ipilimumab - CHECKMATE-227 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and ipilimumab group (range: 494 to 556 patients) and chemotherapy group (range: 469 to 542 patients). Laboratory Abnormality OPDIVO and Ipilimumab Platinum-Doublet Chemotherapy Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Hematology Anemia 46 3.6 78 14 Lymphopenia 46 5 60 15 Chemistry Hyponatremia 41 12 26 4.9 Increased AST 39 5 26 0.4 Increased ALT 36 7 27 0.7 Increased lipase 35 14 14 3.4 Increased alkaline phosphatase 34 3.8 20 0.2 Increased amylase 28 9 18 1.9 Hypocalcemia 28 1.7 17 1.3 Hyperkalemia 27 3.4 22 0.4 Increased creatinine 22 0.9 17 0.2 First-line Treatment of Metastatic or Recurrent NSCLC: In Combination with Ipilimumab and Platinum-Doublet Chemotherapy The safety of OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy was evaluated in CHECKMATE-9LA [see Clinical Studies (14.5) ] . Patients received either OPDIVO 360 mg administered every 3 weeks in combination with ipilimumab 1 mg/kg administered every 6 weeks and platinum-doublet chemotherapy administered every 3 weeks for 2 cycles; or platinum-doublet chemotherapy administered every 3 weeks for 4 cycles. The median duration of therapy in OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy was 6 months (range: 1 day to 19 months): 50% of patients received OPDIVO and ipilimumab for >6 months and 13% of patients received OPDIVO and ipilimumab for >1 year. Serious adverse reactions occurred in 57% of patients who were treated with OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy. The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia. Study therapy with OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy was permanently discontinued for adverse reactions in 24% of patients and 56% had at least one treatment withheld for an adverse reaction. The most common (>20%) adverse reactions were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus. Tables 19 and 20 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9LA. Table 19: Adverse Reactions in >10% of Patients Receiving OPDIVO and Ipilimumab and Platinum-Doublet Chemotherapy - CHECKMATE-9LA Toxicity was graded per NCI CTCAE v4. a Includes fatigue and asthenia. b Includes myalgia, back pain, pain in extremity, musculoskeletal pain, bone pain, flank pain, muscle spasms, musculoskeletal chest pain, musculoskeletal disorder, osteitis, musculoskeletal stiffness, non-cardiac chest pain, arthralgia, arthritis, arthropathy, joint effusion, psoriatic arthropathy, synovitis. c Includes colitis, ulcerative colitis, diarrhea, and enterocolitis. d Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, and gastrointestinal pain. e Includes acne, dermatitis, acneiform dermatitis, allergic dermatitis, atopic dermatitis, bullous dermatitis, generalized exfoliative dermatitis, eczema, keratoderma blennorrhagica, palmar-plantar erythrodysesthesia syndrome, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, morbilliform rash, papular rash, pruritic rash, skin exfoliation, skin reaction, skin toxicity, Stevens-Johnson syndrome, urticaria. f Includes pruritus and generalized pruritus. g Includes cough, productive cough, and upper-airway cough syndrome. h Includes dyspnea, dyspnea at rest, and exertional dyspnea. i Includes autoimmune thyroiditis, increased blood thyroid stimulating hormone, hypothyroidism, thyroiditis, and decreased free tri-iodothyronine. j Includes dizziness, vertigo and positional vertigo. Adverse Reaction OPDIVO and Ipilimumab and Platinum-Doublet Chemotherapy (n=358) Platinum-Doublet Chemotherapy (n=349) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue a 49 5 40 4.9 Pyrexia 14 0.6 10 0.6 Musculoskeletal and Connective Tissue Musculoskeletal pain b 39 4.5 27 2 Gastrointestinal Nausea 32 1.7 41 0.9 Diarrhea c 31 6 18 1.7 Constipation 21 0.6 23 0.6 Vomiting 18 2 17 1.4 Abdominal pain d 12 0.6 11 0.9 Skin and Subcutaneous Tissue Rash e 30 4.7 10 0.3 Pruritus f 21 0.8 2.9 0 Alopecia 11 0.8 10 0.6 Metabolism and Nutrition Decreased appetite 28 2 22 1.7 Respiratory, Thoracic and Mediastinal Cough g 19 0.6 15 0.9 Dyspnea h 18 4.7 14 3.2 Endocrine Hypothyroidism i 19 0.3 3.4 0 Nervous System Headache 11 0.6 7 0 Dizziness j 11 0.6 6 0 Table 20: Laboratory Values Worsening from Baseline a Occurring in >20% of Patients on OPDIVO and Ipilimumab and Platinum-Doublet Chemotherapy - CHECKMATE-9LA a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and ipilimumab and platinum-doublet chemotherapy group (range: 197 to 347 patients) and platinum-doublet chemotherapy group (range: 191 to 335 patients). Laboratory Abnormality OPDIVO and Ipilimumab and Platinum-Doublet Chemotherapy Platinum-Doublet Chemotherapy Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Hematology Anemia 70 9 74 16 Lymphopenia 41 6 40 11 Neutropenia 40 15 42 15 Leukopenia 36 10 40 9 Thrombocytopenia 23 4.3 24 5 Chemistry Hyperglycemia 45 7 42 2.6 Hyponatremia 37 10 27 7 Increased ALT 34 4.3 24 1.2 Increased lipase 31 12 10 2.2 Increased alkaline phosphatase 31 1.2 26 0.3 Increased amylase 30 7 19 1.3 Increased AST 30 3.5 22 0.3 Hypomagnesemia 29 1.2 33 0.6 Hypocalcemia 26 1.4 22 1.8 Increased creatinine 26 1.2 23 0.6 Hyperkalemia 22 1.7 21 2.1 Second-line Treatment of Metastatic NSCLC The safety of OPDIVO was evaluated in CHECKMATE-017, a randomized open-label, multicenter trial in patients with metastatic squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen and in CHECKMATE-057, a randomized, open-label, multicenter trial in patients with metastatic non-squamous NSCLC and progression on or after one prior platinum doublet-based chemotherapy regimen [see Clinical Studies (14.5) ] . These trials excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or with symptomatic interstitial lung disease. Patients received OPDIVO 3 mg/kg over 60 minutes by intravenous infusion every 2 weeks or docetaxel 75 mg/m 2 intravenously every 3 weeks. The median duration of therapy in OPDIVO-treated patients in CHECKMATE-017 was 3.3 months (range: 1 day to 21.7+ months) and in CHECKMATE-057 was 2.6 months (range: 0 to 24.0+ months). In CHECKMATE-017, 36% of patients received OPDIVO for at least 6 months and 18% of patients received OPDIVO for at least 1 year and in CHECKMATE-057, 30% of patients received OPDIVO for >6 months and 20% of patients received OPDIVO for >1 year. Across both trials, the median age of OPDIVO-treated patients was 61 years (range: 37 to 85); 38% were ≥65 years of age, 61% were male, and 91% were White. Ten percent of patients had brain metastases and ECOG performance status was 0 (26%) or 1 (74%). In CHECKMATE-057, in the OPDIVO arm, seven deaths were due to infection including one case of Pneumocystis jirovecii pneumonia, four were due to pulmonary embolism, and one death was due to limbic encephalitis. Serious adverse reactions occurred in 46% of patients receiving OPDIVO. OPDIVO was discontinued in 11% of patients and was delayed in 28% of patients for an adverse reaction. The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. Across both trials, the most common adverse reactions (≥20%) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. Tables 21 and 22 summarize selected adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-057. Table 21: Adverse Reactions Occurring in ≥10% of OPDIVO-Treated Patients and at a Higher Incidence than Docetaxel (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-017 and CHECKMATE-057 Toxicity was graded per NCI CTCAE v4. Adverse Reaction OPDIVO (n=418) Docetaxel (n=397) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Respiratory, Thoracic and Mediastinal Cough 31 0.7 24 0 Metabolism and Nutrition Decreased appetite 28 1.4 23 1.5 Skin and Subcutaneous Tissue Pruritus 10 0.2 2 0 Other clinically important adverse reactions observed in OPDIVO-treated patients and which occurred at a similar incidence in docetaxel-treated patients and not listed elsewhere in section 6 include: fatigue/asthenia (48% all Grades, 5% Grade 3-4), musculoskeletal pain (33% all Grades), pleural effusion (4.5% all Grades), pulmonary embolism (3.3% all Grades). Table 22: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥10% of OPDIVO-Treated Patients for all NCI CTCAE Grades and at a Higher Incidence than Docetaxel (Between Arm Difference of ≥5% All Grades or ≥2% Grades 3-4) - CHECKMATE-017 and CHECKMATE-057 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 405 to 417 patients) and docetaxel group (range: 372 to 390 patients), except for TSH: OPDIVO group n=314 and docetaxel group n=297. b Not graded per NCI CTCAE v4. Laboratory Abnormality OPDIVO Docetaxel All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Chemistry Hyponatremia 35 7 34 4.9 Increased AST 27 1.9 13 0.8 Increased alkaline phosphatase 26 0.7 18 0.8 Increased ALT 22 1.7 17 0.5 Increased creatinine 18 0 12 0.5 Increased TSH b 14 N/A 6 N/A Malignant Pleural Mesothelioma The safety of OPDIVO in combination with ipilimumab was evaluated in CHECKMATE-743, a randomized, open-label trial in patients with previously untreated unresectable malignant pleural mesothelioma [see Clinical Studies (14.6) ] . Patients received either OPDIVO 3 mg/kg over 30 minutes by intravenous infusion every 2 weeks and ipilimumab 1 mg/kg over 30 minutes by intravenous infusion every 6 weeks for up to 2 years; or platinum-doublet chemotherapy for up to 6 cycles. The median duration of therapy in OPDIVO and ipilimumab-treated patients was 5.6 months (range: 0 to 26.2 months); 48% of patients received OPDIVO and ipilimumab for >6 months and 24% of patients received OPDIVO and ipilimumab for >1 year. Serious adverse reactions occurred in 54% of patients who were treated with OPDIVO in combination with ipilimumab. The most frequent (≥2%) serious adverse reactions were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis and encephalitis. Both OPDIVO and ipilimumab were permanently discontinued due to adverse reactions in 23% of patients and 52% had at least one dose withheld due to an adverse reaction. The most common (≥20%) adverse reactions were fatigue, musculoskeletal pain, rash, diarrhea, dyspnea, nausea, decreased appetite, cough, and pruritus. Tables 23 and 24 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-743. Table 23: Adverse Reactions in ≥10% of Patients Receiving OPDIVO and Ipilimumab - CHECKMATE-743 a Includes fatigue and asthenia. b Includes pyrexia and tumor-associated fever. c Includes edema, generalized edema, peripheral edema, and peripheral swelling. d Includes musculoskeletal pain, back pain, bone pain, flank pain, involuntary muscle contractions, muscle spasms, muscle twitching, musculoskeletal chest pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, polymyalgia rheumatica, and spinal pain. e Includes rash, acne, acneiform dermatitis, allergic dermatitis, atopic dermatitis, autoimmune dermatitis, bullous dermatitis, contact dermatitis, dermatitis, drug eruption, dyshidrotic eczema, eczema, erythematous rash, exfoliative rash, generalized exfoliative dermatitis, generalized rash, granulomatous dermatitis, keratoderma blennorrhagica, macular rash, maculopapular rash, morbilliform rash, nodular rash, papular rash, psoriasiform dermatitis, pruritic rash, pustular rash, skin exfoliation, skin reaction, skin toxicity, Stevens-Johnson syndrome, toxic skin eruption, and urticaria. f Includes pruritus, allergic pruritus, and generalized pruritus. g Includes diarrhea, colitis, enteritis, infectious enteritis, enterocolitis, infectious enterocolitis, microscopic colitis, ulcerative colitis, and viral enterocolitis. h Includes abdominal pain, abdominal discomfort, abdominal tenderness, gastrointestinal pain, lower abdominal pain, and upper abdominal pain. i Includes dyspnea, dyspnea at rest, and exertional dyspnea. j Includes cough, productive cough, and upper-airway cough syndrome. k Includes hypothyroidism, autoimmune thyroiditis, decreased free tri-iodothyronine, increased blood thyroid stimulating hormone, primary hypothyroidism, thyroiditis, and autoimmune hypothyroidism. l Includes upper respiratory tract infection, nasopharyngitis, pharyngitis, and rhinitis. m Includes pneumonia, lower respiratory tract infection, lung infection, aspiration pneumonia, and Pneumocystis jirovecii pneumonia. Adverse Reaction OPDIVO and Ipilimumab (n=300) Chemotherapy (n=284) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue a 43 4.3 45 6 Pyrexia b 18 1.3 4.6 0.7 Edema c 17 0 8 0 Musculoskeletal and Connective Tissue Musculoskeletal pain d 38 3.3 17 1.1 Arthralgia 13 1 1.1 0 Skin and Subcutaneous Tissue Rash e 34 2.7 11 0.4 Pruritus f 21 1 1.4 0 Gastrointestinal Diarrhea g 32 6 12 1.1 Nausea 24 0.7 43 2.5 Constipation 19 0.3 30 0.7 Abdominal pain h 15 1 10 0.7 Vomiting 14 0 18 2.1 Respiratory, Thoracic, and Mediastinal Dyspnea i 27 2.3 16 3.2 Cough j 23 0.7 9 0 Metabolism and Nutrition Decreased appetite 24 1 25 1.4 Endocrine Hypothyroidism k 15 0 1.4 0 Infections and Infestations Upper respiratory tract infection l 12 0.3 7 0 Pneumonia m 10 4 4.2 2.1 Table 24: Laboratory Values Worsening from Baseline a Occurring in ≥20% of Patients on OPDIVO and Ipilimumab - CHECKMATE-743 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and ipilimumab group (range: 109 to 297 patients) and chemotherapy group (range: 90 to 276 patients). Laboratory Abnormality OPDIVO and Ipilimumab Chemotherapy Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Chemistry Hyperglycemia 53 3.7 34 1.1 Increased AST 38 7 17 0 Increased ALT 37 7 15 0.4 Increased lipase 34 13 9 0.8 Hyponatremia 32 8 21 2.9 Increased alkaline phosphatase 31 3.1 12 0 Hyperkalemia 30 4.1 16 0.7 Hypocalcemia 28 0 16 0 Increased amylase 26 5 13 0.9 Increased creatinine 20 0.3 20 0.4 Hematology Lymphopenia 43 8 57 14 Anemia 43 2.4 75 15 Advanced Renal Cell Carcinoma First-line Renal Cell Carcinoma CHECKMATE-214 The safety of OPDIVO with ipilimumab was evaluated in CHECKMATE-214, a randomized open-label trial in 1082 patients with previously untreated advanced RCC received OPDIVO 3 mg/kg over 60 minutes with ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses followed by OPDIVO as a single agent at a dose of 3 mg/kg by intravenous infusion every 2 weeks (n=547) or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (n=535) [see Clinical Studies (14.7) ] . The median duration of treatment was 7.9 months (range: 1 day to 21.4+ months) in OPDIVO and ipilimumab-treated patients and 7.8 months (range: 1 day to 20.2+ months) in sunitinib-treated patients. In this trial, 57% of patients in the OPDIVO and ipilimumab arm were exposed to treatment for >6 months and 38% of patients were exposed to treatment for >1 year. Serious adverse reactions occurred in 59% of patients receiving OPDIVO and ipilimumab. Study therapy was discontinued for adverse reactions in 31% of OPDIVO and ipilimumab patients. Fifty-four percent (54%) of patients receiving OPDIVO and ipilimumab had a dose interruption for an adverse reaction. The most frequent serious adverse reactions reported in ≥2% of patients treated with OPDIVO and ipilimumab were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea. The most common adverse reactions (reported in ≥20% of patients) were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, arthralgia, and decreased appetite. The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of OPDIVO and ipilimumab-treated patients include increased lipase, anemia, increased creatinine, increased ALT, increased AST, hyponatremia, increased amylase, and lymphopenia. Tables 25 and 26 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in >15% of OPDIVO and ipilimumab-treated patients in CHECKMATE-214. Table 25: Adverse Reactions in >15% of Patients Receiving OPDIVO and Ipilimumab - CHECKMATE-214 Toxicity was graded per NCI CTCAE v4. a Includes asthenia. b Includes peripheral edema, peripheral swelling. c Includes dermatitis described as acneiform, bullous, and exfoliative, drug eruption, rash described as exfoliative, erythematous, follicular, generalized, macular, maculopapular, papular, pruritic, and pustular, fixed-drug eruption. d Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain. Adverse Reaction OPDIVO and Ipilimumab (n=547) Sunitinib (n=535) Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Adverse Reaction 99 65 99 76 General Fatigue a 58 8 69 13 Pyrexia 25 0.7 17 0.6 Edema b 16 0.5 17 0.6 Skin and Subcutaneous Tissue Rash c 39 3.7 25 1.1 Pruritus/generalized pruritus 33 0.5 11 0 Gastrointestinal Diarrhea 38 4.6 58 6 Nausea 30 2 43 1.5 Vomiting 20 0.9 28 2.1 Abdominal pain 19 1.6 24 1.9 Constipation 17 0.4 18 0 Musculoskeletal and Connective Tissue Musculoskeletal pain d 37 4 40 2.6 Arthralgia 23 1.3 16 0 Respiratory, Thoracic and Mediastinal Cough/productive cough 28 0.2 25 0.4 Dyspnea/exertional dyspnea 20 2.4 21 2.1 Metabolism and Nutrition Decreased appetite 21 1.8 29 0.9 Nervous System Headache 19 0.9 23 0.9 Endocrine Hypothyroidism 18 0.4 27 0.2 Table 26: Laboratory Values Worsening from Baseline a Occurring in >15% of Patients on OPDIVO and Ipilimumab - CHECKMATE-214 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and ipilimumab group (range: 490 to 538 patients) and sunitinib group (range: 485 to 523 patients). Laboratory Abnormality OPDIVO and Ipilimumab Sunitinib Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Chemistry Increased lipase 48 20 51 20 Increased creatinine 42 2.1 46 1.7 Increased ALT 41 7 44 2.7 Increased AST 40 4.8 60 2.1 Increased amylase 39 12 33 7 Hyponatremia 39 10 36 7 Increased alkaline phosphatase 29 2 32 1 Hyperkalemia 29 2.4 28 2.9 Hypocalcemia 21 0.4 35 0.6 Hypomagnesemia 16 0.4 26 1.6 Hematology Anemia 43 3 64 9 Lymphopenia 36 5 63 14 In addition, among patients with TSH ≤ULN at baseline, a lower proportion of patients experienced a treatment-emergent elevation of TSH > ULN in the OPDIVO and ipilimumab group compared to the sunitinib group (31% and 61%, respectively). CHECKMATE-9ER The safety of OPDIVO with cabozantinib was evaluated in CHECKMATE-9ER, a randomized, open-label study in patients with previously untreated advanced RCC. Patients received OPDIVO 240 mg over 30 minutes every 2 weeks with cabozantinib 40 mg orally once daily (n=320) or sunitinib 50 mg daily, administered orally for 4 weeks on treatment followed by 2 weeks off (n=320) [see Clinical Studies (14.7) ] . Cabozantinib could be interrupted or reduced to 20 mg daily or 20 mg every other day. The median duration of treatment was 14 months (range: 0.2 to 27 months) in OPDIVO and cabozantinib-treated patients. In this trial, 82% of patients in the OPDIVO and cabozantinib arm were exposed to treatment for >6 months and 60% of patients were exposed to treatment for >1 year. Serious adverse reactions occurred in 48% of patients receiving OPDIVO and cabozantinib. The most frequent (≥2%) serious adverse reactions were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients. Adverse reactions leading to discontinuation of either OPDIVO or cabozantinib occurred in 20% of patients: 7% OPDIVO only, 8% cabozantinib only, and 6% both drugs due to same adverse reaction at the same time. Adverse reaction leading to dose interruption or reduction of either OPDIVO or cabozantinib occurred in 83% of patients: 3% OPDIVO only, 46% cabozantinib only, and 21% both drugs due to same adverse reaction at the same time, and 6% both drugs sequentially. The most common adverse reactions reported in ≥20% of patients treated with OPDIVO and cabozantinib were diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection. Tables 27 and 28 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9ER. Table 27: Adverse Reactions in >15% of Patients Receiving OPDIVO and Cabozantinib - CHECKMATE-9ER Toxicity was graded per NCI CTCAE v4. a Includes abdominal discomfort, abdominal pain lower, abdominal pain upper. b Includes gastroesophageal reflux disease. c Includes asthenia. d Includes hepatotoxicity, ALT increased, AST increased, blood alkaline phosphatase increased, gamma-glutamyl transferase increased, autoimmune hepatitis, blood bilirubin increased, drug induced liver injury, hepatic enzyme increased, hepatitis, hyperbilirubinemia, liver function test increased, liver function test abnormal, transaminases increased, hepatic failure. e Includes mucosal inflammation, aphthous ulcer, mouth ulceration. f Includes dermatitis, dermatitis acneiform, dermatitis bullous, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pruritic. g Includes blood pressure increased, blood pressure systolic increased. h Includes primary hypothyroidism. i Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain. j Includes productive cough. k Includes nasopharyngitis, pharyngitis, rhinitis. Adverse Reaction OPDIVO and Cabozantinib (n=320) Sunitinib (n=320) Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Gastrointestinal Diarrhea 64 7 47 4.4 Nausea 27 0.6 31 0.3 Abdominal pain a 22 1.9 15 0.3 Vomiting 17 1.9 21 0.3 Dyspepsia b 15 0 22 0.3 General Fatigue c 51 8 50 8 Hepatobiliary Hepatotoxicity d 44 11 26 5 Skin and Subcutaneous Tissue Palmar-plantar erythrodysesthesia syndrome 40 8 41 8 Stomatitis e 37 3.4 46 4.4 Rash f 36 3.1 14 0 Pruritus 19 0.3 4.4 0 Vascular Hypertension g 36 13 39 14 Endocrine Hypothyroidism h 34 0.3 30 0.3 Musculoskeletal and Connective Tissue Musculoskeletal pain i 33 3.8 29 3.1 Arthralgia 18 0.3 9 0.3 Metabolism and Nutrition Decreased appetite 28 1.9 20 1.3 Nervous System Dysgeusia 24 0 22 0 Headache 16 0 12 0.6 Respiratory, Thoracic and Mediastinal Cough j 20 0.3 17 0 Dysphonia 17 0.3 3.4 0 Infections and Infestations Upper respiratory tract infection k 20 0.3 8 0.3 Table 28: Laboratory Values Worsening from Baseline a Occurring in >20% of Patients on OPDIVO and Cabozantinib - CHECKMATE-9ER a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and cabozantinib group (range: 170 to 317 patients) and sunitinib group (range: 173 to 311 patients). Laboratory Abnormality OPDIVO and Cabozantinib Sunitinib Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Chemistry Increased ALT 79 9.8 39 3.5 Increased AST 77 7.9 57 2.6 Hypophosphatemia 69 28 48 10 Hypocalcemia 54 1.9 24 0.6 Hypomagnesemia 47 1.3 25 0.3 Hyperglycemia 44 3.5 44 1.7 Hyponatremia 43 11 36 12 Increased lipase 41 14 38 13 Increased amylase 41 10 28 6 Increased alkaline phosphatase 41 2.8 37 1.6 Increased creatinine 39 1.3 42 0.6 Hyperkalemia 35 4.7 27 1 Hypoglycemia 26 0.8 14 0.4 Hematology Lymphopenia 42 6.6 45 10 Thrombocytopenia 41 0.3 70 9.7 Anemia 37 2.5 61 4.8 Leukopenia 37 0.3 66 5.1 Neutropenia 35 3.2 67 12 Previously Treated Renal Cell Carcinoma CHECKMATE-025 The safety of OPDIVO was evaluated in CHECKMATE-025, a randomized open-label trial in 803 patients with advanced RCC who had experienced disease progression during or after at least one anti-angiogenic treatment regimen received OPDIVO 3 mg/kg over 60 minutes by intravenous infusion every 2 weeks (n=406) or everolimus 10 mg daily (n=397) [see Clinical Studies (14.7) ] . The median duration of treatment was 5.5 months (range: 1 day to 29.6+ months) in OPDIVO-treated patients and 3.7 months (range: 6 days to 25.7+ months) in everolimus-treated patients. Rate of death on treatment or within 30 days of the last dose was 4.7% on the OPDIVO arm. Serious adverse reactions occurred in 47% of patients receiving OPDIVO. Study therapy was discontinued for adverse reactions in 16% of OPDIVO patients. Forty-four percent (44%) of patients receiving OPDIVO had a dose interruption for an adverse reaction. The most frequent serious adverse reactions in at least 2% of patients were: acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. The most common adverse reactions (≥20%) were fatigue, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, and arthralgia. The most common laboratory abnormalities which have worsened compared to baseline in ≥30% of patients include increased creatinine, lymphopenia, anemia, increased AST, increased alkaline phosphatase, hyponatremia, increased triglycerides, and hyperkalemia. In addition, among patients with TSH < ULN at baseline, a greater proportion of patients experienced a treatment-emergent elevation of TSH >ULN in the OPDIVO group compared to the everolimus group (26% and 14%, respectively). Tables 29 and 30 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-025. Table 29: Adverse Reactions in >15% of Patients Receiving OPDIVO - CHECKMATE-025 Toxicity was graded per NCI CTCAE v4. a Includes asthenia, decreased activity, fatigue, and malaise. b Includes nasopharyngitis, pharyngitis, rhinitis, and viral upper respiratory infection (URI). c Includes colitis, enterocolitis, and gastroenteritis. d Includes dermatitis, acneiform dermatitis, erythematous rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, erythema multiforme, and erythema. Adverse Reaction OPDIVO (n=406) Everolimus (n=397) Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Adverse Reaction 98 56 96 62 General Fatigue a 56 6 57 7 Pyrexia 17 0.7 20 0.8 Respiratory, Thoracic and Mediastinal Cough/productive cough 34 0 38 0.5 Dyspnea/exertional dyspnea 27 3 31 2 Upper respiratory infection b 18 0 11 0 Gastrointestinal Nausea 28 0.5 29 1 Diarrhea c 25 2.2 32 1.8 Constipation 23 0.5 18 0.5 Vomiting 16 0.5 16 0.5 Skin and Subcutaneous Tissue Rash d 28 1.5 36 1 Pruritus/generalized pruritus 19 0 14 0 Metabolism and Nutrition Decreased appetite 23 1.2 30 1.5 Musculoskeletal and Connective Tissue Arthralgia 20 1 14 0.5 Back pain 21 3.4 16 2.8 Other clinically important adverse reactions in CHECKMATE-025 were: General Disorders and Administration Site Conditions: peripheral edema/edema Gastrointestinal Disorders: abdominal pain/discomfort Musculoskeletal and Connective Tissue Disorders: extremity pain, musculoskeletal pain Nervous System Disorders: headache/migraine, peripheral neuropathy Investigations: weight decreased Skin Disorders: palmar-plantar erythrodysesthesia Table 30: Laboratory Values Worsening from Baseline a Occurring in >15% of Patients on OPDIVO - CHECKMATE-025 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 259 to 401 patients) and everolimus group (range: 257 to 376 patients). Laboratory Abnormality OPDIVO Everolimus Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Hematology Lymphopenia 42 6 53 11 Anemia 39 8 69 16 Chemistry Increased creatinine 42 2 45 1.6 Increased AST 33 2.8 39 1.6 Increased alkaline phosphatase 32 2.3 32 0.8 Hyponatremia 32 7 26 6 Hyperkalemia 30 4 20 2.1 Hypocalcemia 23 0.9 26 1.3 Increased ALT 22 3.2 31 0.8 Hypercalcemia 19 3.2 6 0.3 Lipids Increased triglycerides 32 1.5 67 11 Increased cholesterol 21 0.3 55 1.4 Classical Hodgkin Lymphoma Previously Untreated Classical Hodgkin Lymphoma The safety of OPDIVO in combination with AVD in patients with previously untreated cHL was evaluated in Study CA209-8UT (SWOG 1826) [see Clinical Studies (14.8)] . Patients received either OPDIVO in combination with AVD every 2 weeks for 6 cycles or brentuximab vedotin (BV) in combination with AVD every 2 weeks for 6 cycles. Patients aged 18 years or older (n=370) received an OPDIVO dosage of 240 mg, and patients aged 12-17 years (n=120) received OPDIVO 3 mg/kg (maximum 240 mg). Primary GCSF prophylaxis was administered to 41% of the OPDIVO + AVD arm and 98% of the BV + AVD arm. In recipients of OPDIVO + AVD, serious adverse reactions occurred in 39% of patients, most often (in ≥5% of patients) from neutropenia (7%), pyrexia (7%), febrile neutropenia (6%), and nausea (6%). Fatal adverse reactions occurred in 0.6%, all from sepsis. Adverse reactions led to dose modification of OPDIVO in 12% of patients (most often from infection) and permanent discontinuation of OPDIVO in 3.9% (most often from hepatic events). Immune-mediated adverse reactions occurred in 9% of patients (Grade 3-4, 2.7%) and were treated with systemic immunosuppressants in 61% of cases. The most common (≥30%) adverse reactions in the OPDIVO + AVD arm included nausea, neutropenia, fatigue, anemia, constipation, leukopenia, musculoskeletal pain, peripheral neuropathy, transaminases increase, vomiting, and stomatitis. Table 31 summarizes selected adverse reactions in Study CA209-8UT. Rates of lab-related adverse reactions are based on safety reporting without laboratory datasets. Table 31: Adverse Reactions in ≥15% of Patients with cHL Receiving OPDIVO in Combination with AVD – CA209-8UT Toxicity was graded per NCI CTCAE v5. a Represents a composite of multiple related terms. b Rates based on adverse event reporting. Adverse Reaction OPDIVO and AVD (n=490) Brentuximab Vedotin and AVD (n=490) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Gastrointestinal Nausea 70 1.6 74 3.5 Constipation 49 0.2 50 1.8 Vomiting 33 2.0 38 2.9 Stomatitis 30 2.0 28 2.7 Diarrhea 27 2.0 36 2.2 Abdominal pain 22 1.0 37 3.1 Dyspepsia 20 0 17 0 Blood and Lymphatic Systems a, b Neutropenia 61 51 36 28 Anemia 51 7 53 10 Leukopenia 44 16 30 14 Lymphopenia 25 8 27 9 General Fatigue 59 1.0 58 2.4 Pyrexia 21 1.0 20 0.6 Hepatobiliary b Transaminases increase a 41 6 53 7 Blood alkaline phosphatase increase 17 0 23 0 Musculoskeletal and Connective Tissue Musculoskeletal pain a 42 1.6 55 4.1 Arthralgia 18 0.2 17 1.4 Nervous System Peripheral neuropathy a 41 1.2 66 8 Headache 24 1.0 25 1.2 Metabolism and Nutrition Hyperglycemia b 29 0.8 31 2.0 Decreased appetite 16 0.4 26 1.6 Skin and Subcutaneous Tissue Rash a 25 1.0 28 0.2 Alopecia 23 0 28 0 Pruritus 17 0 14 0 Respiratory, Thoracic, and Mediastinal Cough 26 0 24 0.2 Dyspnea 22 1.2 24 1.6 Vascular Disorders Hypertension 16 2.4 17 3.9 Other clinically relevant adverse reactions in the OPDIVO + AVD arm included thrombocytopenia (12%), COVID-19 infection (10%), immune-mediated adverse reactions including endocrine (4.3%) and non-endocrine (5%) events, pneumonia (3.7%), and sepsis (2.9%). In the OPDIVO + AVD arm, adverse reactions occurring at least 10% more frequently in pediatric patients compared to adult patients included: nausea (78%), anemia (61%), transaminases increased (58%), vomiting (51%), lymphopenia (33%), pyrexia (33%), hyperphosphatemia (15%), and eosinophilia (13%). Relapsed or Refractory Classical Hodgkin Lymphoma The safety of OPDIVO was evaluated in 266 adult patients with relapsed or refractory cHL (243 patients in the CHECKMATE-205 and 23 patients in the CHECKMATE-039 trials) [see Clinical Studies (14.8) ] . Patients received OPDIVO 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression, maximal clinical benefit, or unacceptable toxicity. The median age was 34 years (range: 18 to 72), 98% of patients had received autologous HSCT, none had received allogeneic HSCT, and 74% had received brentuximab vedotin. The median number of prior systemic regimens was 4 (range: 2 to 15). Patients received a median of 23 doses (cycles) of OPDIVO (range: 1 to 48), with a median duration of therapy of 11 months (range: 0 to 23 months). Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last nivolumab dose, 2 from infection 8 to 9 months after completing nivolumab, and 6 from complications of allogeneic HSCT. Serious adverse reactions occurred in 26% of patients. Dose delay for an adverse reaction occurred in 34% of patients. OPDIVO was discontinued due to adverse reactions in 7% of patients. The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. The most common adverse reactions (≥20%) among all patients were upper respiratory tract infection, fatigue, cough, diarrhea, pyrexia, musculoskeletal pain, rash, nausea, and pruritus. Tables 32 and 33 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-205 and CHECKMATE-039. Table 32: Adverse Reactions Occurring in ≥10% of Patients with Relapsed or Refractory cHL - CHECKMATE-205 and CHECKMATE-039 Toxicity was graded per NCI CTCAE v4. a Includes events occurring up to 30 days after last nivolumab dose, regardless of causality. After an immune-mediated adverse reaction, reactions following nivolumab rechallenge were included if they occurred up to 30 days after completing the initial nivolumab course. b Includes nasopharyngitis, pharyngitis, rhinitis, and sinusitis. c Includes pneumonia bacterial, pneumonia mycoplasmal, pneumocystis jirovecii pneumonia. d Includes asthenia. e Includes colitis. f Includes abdominal discomfort and upper abdominal pain. g Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, and pain in extremity. h Includes dermatitis, dermatitis acneiform, dermatitis exfoliative, and rash described as macular, papular, maculopapular, pruritic, exfoliative, or acneiform. i Includes hyperesthesia, hypoesthesia, paresthesia, dysesthesia, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy. These numbers are specific to treatment-emergent events. Adverse Reaction a OPDIVO (n=266) All Grades (%) Grades 3-4 (%) Infections Upper respiratory tract infection b 44 0.8 Pneumonia/bronchopneumonia c 13 3.8 Nasal congestion 11 0 General Fatigue d 39 1.9 Pyrexia 29 <1 Respiratory, Thoracic and Mediastinal Cough/productive cough 36 0 Dyspnea/exertional dyspnea 15 1.5 Gastrointestinal Diarrhea e 33 1.5 Nausea 20 0 Vomiting 19 <1 Abdominal pain f 16 <1 Constipation 14 0.4 Musculoskeletal and Connective Tissue Musculoskeletal pain g 26 1.1 Arthralgia 16 <1 Skin and Subcutaneous Tissue Rash h 24 1.5 Pruritus 20 0 Nervous System Headache 17 <1 Neuropathy peripheral i 12 <1 Injury, Poisoning and Procedural Complications Infusion-related reaction 14 <1 Endocrine Hypothyroidism/thyroiditis 12 0 Additional information regarding clinically important adverse reactions: Immune-mediated pneumonitis: In CHECKMATE-205 and CHECKMATE-039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO (one Grade 3 and 12 Grade 2). The median time to onset was 4.5 months (range: 5 days to 12 months). All 13 patients received systemic corticosteroids, with resolution in 12. Four patients permanently discontinued OPDIVO due to pneumonitis. Eight patients continued OPDIVO (three after dose delay), of whom two had recurrence of pneumonitis. Peripheral neuropathy: Treatment-emergent peripheral neuropathy was reported in 12% (31/266) of all patients receiving OPDIVO. Twenty-eight patients (11%) had new-onset peripheral neuropathy and 3 patients had worsening of neuropathy from baseline. The median time to onset was 50 (range: 1 to 309) days. Complications of allogeneic HSCT after OPDIVO: Of 17 patients with cHL from the CHECKMATE-205 and CHECKMATE-039 trials who underwent allogeneic HSCT after treatment with OPDIVO, 6 patients (35%) died from transplant-related complications. Five deaths occurred in the setting of severe (Grade 3 to 4) or refractory GVHD. Hyperacute GVHD occurred in 2 patients (12%) and Grade 3 or higher GVHD was reported in 5 patients (29%). Hepatic VOD occurred in 1 patient, who received reduced-intensity conditioned allogeneic HSCT and died of GVHD and multi-organ failure. Table 33 summarizes laboratory abnormalities in patients with cHL. The most common (≥20%) treatment-emergent laboratory abnormalities included cytopenias, liver function abnormalities, and increased lipase. Other common findings (≥10%) included increased creatinine, electrolyte abnormalities, and increased amylase. Table 33: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥10% of Patients - CHECKMATE-205 and CHECKMATE-039 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement: range: 203 to 266 patients. b Includes events occurring up to 30 days after last nivolumab dose. After an immune-mediated adverse reaction, reactions following nivolumab rechallenge were included if they occurred within 30 days of completing the initial nivolumab course. c In addition, in the safety population, fasting hyperglycemia (all grade 1-2) was reported in 27 of 69 (39%) evaluable patients and fasting hypoglycemia (all grade 1-2) in 11 of 69 (16%). Laboratory Abnormality OPDIVO a (n=266) All Grades (%) b Grades 3-4 (%) b Hematology Leukopenia 38 4.5 Neutropenia 37 5 Thrombocytopenia 37 3 Lymphopenia 32 11 Anemia 26 2.6 Chemistry c Increased AST 33 2.6 Increased ALT 31 3.4 Increased lipase 22 9 Increased alkaline phosphatase 20 1.5 Hyponatremia 20 1.1 Hypokalemia 16 1.9 Increased creatinine 16 <1 Hypocalcemia 15 <1 Hyperkalemia 15 1.5 Hypomagnesemia 14 <1 Increased amylase 13 1.5 Increased bilirubin 11 1.5 Squamous Cell Carcinoma of the Head and Neck The safety of OPDIVO was evaluated in CHECKMATE-141, a randomized, active-controlled, open-label, multicenter trial in patients with recurrent or metastatic SCCHN with progression during or within 6 months of receiving prior platinum-based therapy [see Clinical Studies (14.9) ] . The trial excluded patients with active autoimmune disease, medical conditions requiring systemic immunosuppression, or recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology, salivary gland or non-squamous histologies (e.g., mucosal melanoma). Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks (n=236) or investigator’s choice of either cetuximab (400 mg/m 2 initial dose intravenously followed by 250 mg/m 2 weekly), or methotrexate (40 to 60 mg/m 2 intravenously weekly), or docetaxel (30 to 40 mg/m 2 intravenously weekly). The median duration of exposure to nivolumab was 1.9 months (range: 1 day to 16.1+ months) in OPDIVO-treated patients. In this trial, 18% of patients received OPDIVO for >6 months and 2.5% of patients received OPDIVO for >1 year. The median age of all randomized patients was 60 years (range: 28 to 83); 28% of patients in the OPDIVO group were ≥65 years of age and 37% in the comparator group were ≥65 years of age, 83% were male and 83% were White, 12% were Asian, and 4% were Black. Baseline ECOG performance status was 0 (20%) or 1 (78%), 45% of patients received only one prior line of systemic therapy, the remaining 55% of patients had two or more prior lines of therapy, and 90% had prior radiation therapy. Serious adverse reactions occurred in 49% of patients receiving OPDIVO. OPDIVO was discontinued in 14% of patients and was delayed in 24% of patients for an adverse reaction. Adverse reactions and laboratory abnormalities occurring in patients with SCCHN were generally similar to those occurring in patients with melanoma and NSCLC. The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. The most common adverse reactions occurring in ≥10% of OPDIVO-treated patients and at a higher incidence than investigator’s choice were cough and dyspnea. The most common laboratory abnormalities occurring in ≥10% of OPDIVO-treated patients and at a higher incidence than investigator’s choice were increased alkaline phosphatase, increased amylase, hypercalcemia, hyperkalemia, and increased TSH. Adjuvant Treatment of Urothelial Carcinoma (UC) The safety of OPDIVO was evaluated in CHECKMATE-274, a randomized, double-blind, multicenter trial of adjuvant OPDIVO versus placebo in adult patients who had undergone radical resection of UC originating in the bladder or upper urinary tract (renal pelvis or ureter) and were at high risk of recurrence [see Clinical Studies (14.10) ] . Patients received OPDIVO 240 mg by intravenous infusion over 30 minutes every 2 weeks (n=351) or placebo (n=348) until recurrence or unacceptable toxicity for a maximum of 1 year. The median duration of OPDIVO treatment was 8.8 months (range: 0 to 12.5). Serious adverse reactions occurred in 30% of OPDIVO patients. The most frequent serious adverse reaction reported in ≥2% of patients was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%). OPDIVO was discontinued for adverse reactions in 18% of patients. OPDIVO was delayed for adverse reaction in 33% of patients. The most common adverse reactions (reported in ≥20% of patients) were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and urinary tract infection. Tables 34 and 35 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-274. Table 34: Adverse Reactions Occurring in ≥10% of Patients - CHECKMATE-274 Toxicity was graded per NCI CTCAE v4. a Includes acne, blister, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis contact, eczema, eczema asteatotic, eczema nummular, erythema, erythema multiforme, lichen sclerosus, lichenoid keratosis, pemphigoid, photosensitivity reaction, pigmentation disorder, psoriasis, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rosacea, skin exfoliation, skin lesion, skin reaction, toxic skin eruption, and urticaria. b Includes colitis, colitis microscopic, diarrhea, duodenitis, enteritis, immune-mediated enterocolitis. c Includes abdominal pain, abdominal discomfort, abdominal tenderness, lower and upper abdominal pain. d Includes musculoskeletal pain, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain. e Includes cystitis, escherichia urinary tract infection, pyelonephritis, pyelonephritis acute, pyelonephritis chronic, urethritis, urinary tract infection, urinary tract infection bacterial, urinary tract infection staphylococcal, and urosepsis. f Includes upper respiratory tract infection, nasopharyngitis, pharyngitis and rhinitis. g Includes acute kidney injury, autoimmune nephritis, blood creatinine increased, glomerular filtration rate decreased, immune-mediated nephritis, nephritis, renal failure, and renal impairment. h Includes cough, productive cough, and upper-airway cough syndrome. i Includes dyspnea and exertional dyspnea. j Includes dizziness, postural dizziness and vertigo. k Includes aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, cholangitis, drug-induced liver injury, hepatic failure, hepatic function abnormal, hepatitis, hepatocellular injury, hyperbilirubinemia, gamma-glutamyl transferase increased, liver injury, and transaminases increased. Adverse Reaction OPDIVO (n=351) Placebo (n=348) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Skin and Subcutaneous Tissue Rash a 36 1.7 19 0.3 Pruritus 30 0 16 0 General Fatigue/Asthenia 36 1.1 32 0.3 Pyrexia 10 0.3 10 0.3 Gastrointestinal Diarrhea b 30 2.8 27 1.7 Nausea 16 0.6 13 0 Abdominal pain c 15 0.9 15 0.6 Constipation 13 0.3 15 0.3 Musculoskeletal and Connective Tissue Musculoskeletal pain d 28 0.6 24 0.9 Arthralgia 11 0.3 13 0 Infections Urinary tract infection e 22 6 23 9 Upper respiratory tract infection f 16 0.3 16 0.6 Endocrine Hyperthyroidism 11 0 1.1 0 Hypothyroidism 11 0 2.3 0 Renal and Urinary Disorders Renal dysfunction g 17 1.7 16 0.9 Respiratory, Thoracic and Mediastinal Cough h 14 0 11 0 Dyspnea i 11 0.3 6 0.3 Metabolism and Nutrition Decreased appetite 13 0.9 7 0.3 Nervous System Disorders Dizziness j 11 0.3 9 0 Hepatobiliary Hepatitis k 11 4 8 0.6 Table 35: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥10% of Patients - CHECKMATE-274 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 322 to 348 patients) and placebo group (range: 312 to 341 patients). Laboratory Abnormality OPDIVO (n=351) Placebo (n=348) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Chemistry Increased creatinine 36 1.7 36 2.6 Increased amylase 34 8 23 3.2 Increased lipase 33 12 31 10 Hyperkalemia 32 5 30 6 Increased alkaline phosphatase 24 2.3 15 0.6 Increased AST 24 3.5 16 0.9 Increased ALT 23 2.9 15 0.6 Hyponatremia 22 4.1 17 1.8 Hypocalcemia 17 1.2 11 0.9 Hypomagnesemia 16 0 9 0 Hypercalcemia 12 0.3 8 0.3 Hematology Lymphopenia 33 2.9 27 1.5 Anemia 30 1.4 28 0.9 Neutropenia 11 0.6 10 0.3 First-line Treatment of Unresectable or Metastatic UC The safety of OPDIVO was evaluated in CHECKMATE-901, a randomized, open-label trial in cisplatin-eligible patients with unresectable or metastatic UC [see Clinical Studies (14.10) ] . Patients received either OPDIVO 360 mg with cisplatin and gemcitabine every 3 weeks for up to 6 cycles followed by single-agent OPDIVO 480 mg every 4 weeks up to 2 years (n=304), or cisplatin and gemcitabine chemotherapy every 3 weeks for up to 6 cycles (n=288). Patients discontinuing cisplatin alone were permitted to switch to carboplatin. Among patients who received OPDIVO with chemotherapy, the median duration of OPDIVO exposure was 7.4 months (range: 0.03 to 47.9 months). Serious adverse reactions occurred in 48% of patients receiving OPDIVO in combination with chemotherapy. The most frequent serious adverse reactions reported in ≥2% of patients who received OPDIVO with chemotherapy were urinary tract infection (4.9%), acute kidney injury (4.3%), anemia (3%), pulmonary embolism (2.6%), sepsis (2.3%), and platelet count decreased (2.3%). The most common adverse reactions (reported in ≥20% of patients) were nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, and peripheral neuropathy. Fatal adverse reactions occurred in 3.6% of patients who received OPDIVO in combination with chemotherapy; these included sepsis (1%). OPDIVO and/or chemotherapy were discontinued in 30% of patients and were delayed in 67% of patients for an adverse reaction. Tables 36 and 37 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-901. Table 36: Adverse Reactions Occurring in ≥10% of Treated Patients - CHECKMATE-901 Toxicity was graded per NCI CTCAE v4. a Includes colitis, immune-mediated enterocolitis. b Includes upper abdominal pain, lower abdominal pain, abdominal discomfort, epigastric discomfort, gastrointestinal pain, and hepatic pain. c Includes asthenia. d Includes peripheral edema, swelling, peripheral swelling, localized edema, swelling, face edema, testicular edema, gravitational edema, and edema genital. e Includes hyperthermia, body temperature increased and hyperpyrexia. f Includes back pain, arthralgia, bone pain, arthritis, musculoskeletal chest pain, non-cardiac chest pain, myalgia, neck pain, pain in extremity, and spinal pain. g Includes maculopapular rash, erythematous rash, macular rash, papular rash, pustular rash, acneiform dermatitis, dermatitis, allergic dermatitis, atopic dermatitis, exfoliative rash, eczema asteatotic, erythema multiforme, palmar-plantar erythrodysesthesia syndrome, eczema, dermatitis exfoliative generalized, and skin exfoliation. h Includes paresthesia, peripheral sensory neuropathy, hypoesthesia, dysesthesia, neuralgia, hyperesthesia, peripheral motor neuropathy, polyneuropathy. i Includes occipital neuralgia. j Includes urosepsis, cystitis, pyelonephritis, pyelonephritis acute, urinary tract infection enterococcal, escherichia urinary tract infection. k Includes blood stimulating hormone increased. l Includes acute kidney injury, renal failure, renal impairment, glomerular filtration rate decreased, anuria, azotemia. Adverse Reaction OPDIVO and Platinum-Doublet Chemotherapy (n=304) Platinum-Doublet Chemotherapy (n=288) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Gastrointestinal disorders Nausea 52 0.3 53 1 Constipation 30 0 28 0.7 Vomiting 23 1.3 19 2.1 Diarrhea a 19 2 14 0 Abdominal pain b 14 0.3 9 0.3 General Fatigue c 48 3.9 43 4.2 Edema d 18 0 9 0.3 Pyrexia e 14 1 14 0 Musculoskeletal and Connective Tissue Musculoskeletal pain f 33 3 21 0.3 Metabolism and Nutrition Decreased appetite 30 1.6 19 1 Skin and Subcutaneous Tissue Rash g 25 2.3 7 0.3 Pruritus 17 0.7 3.5 0 Nervous System Disorders Peripheral neuropathy h 20 0.7 14 0 Headache i 11 0 5 0 Infections Urinary tract infection j 19 8 18 8 Endocrine disorders Hypothyroidism k 17 0 0.3 0 Renal and Urinary Disorders Renal dysfunction l 14 6 11 1.7 Hematuria 11 1 7 1.4 Investigations Weight decreased 11 0.3 6 0 Table 37: Selected Laboratory Abnormalities Worsening from Baseline a Occurring in ≥20% of Patients - CHECKMATE-901 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 289-301 patients) and chemotherapy group (range: 265-281 patients). Laboratory Abnormality OPDIVO and Platinum-Doublet Chemotherapy (n=304) Platinum-Doublet Chemotherapy (n=288) Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Hematology Anemia 88 21 80 21 Neutropenia 82 35 76 28 Lymphopenia 71 17 56 13 Thrombocytopenia 60 13 51 8 Chemistry Increased creatinine 53 2.4 42 1.1 Hypomagnesemia 48 3.8 39 1.5 Hyponatremia 43 13 39 8 Hyperglycemia 41 3.9 37 3.2 Hypocalcemia 36 2.1 24 1.1 Hyperkalemia 33 3.0 32 1.1 Increased amylase 32 4.2 23 3.6 Increased AST 31 2.4 17 0.7 Increased ALT 29 2.4 19 0.7 Previously Treated Advanced or Metastatic UC The safety of OPDIVO was evaluated in CHECKMATE-275, a single arm trial in which 270 patients with locally advanced or metastatic UC had disease progression during or following platinum-containing chemotherapy or had disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy [see Clinical Studies (14.10) ] . Patients received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity. The median duration of treatment was 3.3 months (range: 0 to 13.4+). Forty-six percent (46%) of patients had a dose interruption for an adverse reaction. Fourteen patients (5.2%) died from causes other than disease progression. This includes 4 patients (1.5%) who died from pneumonitis or cardiovascular failure which was attributed to treatment with OPDIVO. Serious adverse reactions occurred in 54% of patients. OPDIVO was discontinued for adverse reactions in 17% of patients. The most frequent serious adverse reactions reported in ≥2% of patients were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. The most common adverse reactions (reported in ≥20% of patients) were fatigue, musculoskeletal pain, nausea, and decreased appetite. Tables 38 and 39 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-275. Table 38: Adverse Reactions Occurring in ≥10% of Patients - CHECKMATE-275 Toxicity was graded per NCI CTCAE v4. a Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity and spinal pain. b Includes abdominal discomfort, lower and upper abdominal pain. c Includes dermatitis, dermatitis acneiform, dermatitis bullous, and rash described as generalized, macular, maculopapular, or pruritic. d Includes autoimmune thyroiditis, blood TSH decrease, blood TSH increase, hyperthyroidism, hypothyroidism, thyroiditis, thyroxine decreased, thyroxine free increased, thyroxine increased, tri-iodothyronine free increased, tri-iodothyronine increased. Adverse Reaction OPDIVO (n=270) All Grades (%) Grades 3-4 (%) Adverse Reaction 99 51 General Asthenia/fatigue/malaise 46 7 Pyrexia/tumor associated fever 17 0.4 Edema/peripheral edema/peripheral swelling 13 0.4 Musculoskeletal and Connective Tissue Musculoskeletal pain a 30 2.6 Arthralgia 10 0.7 Metabolism and Nutrition Decreased appetite 22 2.2 Gastrointestinal Nausea 22 0.7 Diarrhea 17 2.6 Constipation 16 0.4 Abdominal pain b 13 1.5 Vomiting 12 1.9 Respiratory, Thoracic and Mediastinal Cough/productive cough 18 0 Dyspnea/exertional dyspnea 14 3.3 Infections Urinary tract infection/escherichia/fungal urinary tract infection 17 7 Skin and Subcutaneous Tissue Rash c 16 1.5 Pruritus 12 0 Endocrine Thyroid disorders d 15 0 Table 39: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients - CHECKMATE-275 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: range: 84 to 256 patients. Laboratory Abnormality OPDIVO a All Grades (%) Grades 3-4 (%) Chemistry Hyperglycemia 42 2.4 Hyponatremia 41 11 Increased creatinine 39 2 Increased alkaline phosphatase 33 5.5 Hypocalcemia 26 0.8 Increased AST 24 3.5 Increased lipase 20 7 Hyperkalemia 19 1.2 Increased ALT 18 1.2 Increased amylase 18 4.4 Hypomagnesemia 16 0 Hematology Lymphopenia 42 9 Anemia 40 7 Thrombocytopenia 15 2.4 Leukopenia 11 0 MSI-H or dMMR Metastatic Colorectal Cancer Treatment of MSI-H or dMMR mCRC: In Combination with Ipilimumab The safety of OPDIVO in combination with ipilimumab, or as a single agent, was evaluated in CHECKMATE-8HW, a randomized, open-label, three arm trial in immunotherapy naive patients with MSI-H or dMMR mCRC [see Clinical Studies (14.11) ] . Patients received one of the following: • OPDIVO 240 mg every 3 weeks and ipilimumab 1 mg/kg every 3 weeks for a maximum of 4 doses, then OPDIVO 480 mg every 4 weeks. • OPDIVO 240 mg every 2 weeks for 6 doses, then OPDIVO 480 mg every 4 weeks. • Investigator’s choice chemotherapy: mFOLFOX or FOLFIRI [see Clinical Studies (14.11) ]. In the OPDIVO and ipilimumab arm, the median duration of exposure to OPDIVO was 20.5 months (range: 0 to 35.9 months), 70% of patients were exposed for >6 months and 63% were exposed for >1 year. In the OPDIVO arm, the median duration of exposure to OPDIVO was 16.4 months (range: 0 to 36 months), 64% of patients were exposed for >6 months and 54% were exposed for >1 year. Serious adverse reactions occurred in 46% of patients receiving OPDIVO in combination with ipilimumab, and 39% of patients receiving OPDIVO alone. The most frequent serious adverse reactions reported in ≥1% of patients who received OPDIVO with ipilimumab were adrenal insufficiency (2.8%), hypophysitis (2.8%), diarrhea (2.0%), abdominal pain (2.0%), small intestinal obstruction (2.0%), pneumonia (1.7%), acute kidney injury (1.4%), immune mediated enterocolitis (1.4%), pneumonitis (1.4%), colitis (1.1%), large intestinal obstruction (1.1%), and urinary tract infection (1.1%). The most frequent serious adverse reactions reported in >1% of patients who received OPDIVO, as a single agent, were intestinal obstruction (2.3%), acute kidney injury (1.7%), COVID-19 (1.7%), abdominal pain (1.4%), diarrhea (1.4%), ileus (1.4%), subileus (1.4%), pulmonary embolism (1.4%), adrenal insufficiency (1.1%) and pneumonia (1.1%). Fatal adverse reactions occurred in 2 (0.6%) patients who received OPDIVO in combination with ipilimumab; these included myocarditis, and pneumonitis (1 each). Fatal adverse reactions occurring in 3 (0.9%) patients who received OPDIVO as a single agent; these included pneumonitis (n=2) and myasthenia gravis. OPDIVO and/or ipilimumab were permanently discontinued in 19% of patients receiving the combination. The most frequent adverse reactions (>1%) leading to permanent discontinuation were adrenal insufficiency (1.4%), immune mediated enterocolitis (1.1%), and pneumonitis (1.1%). OPDIVO was permanently discontinued in 13% of patients receiving single agent OPDIVO. Adverse reactions leading to the delay of OPDIVO and/or ipilimumab occurred in 48% of patients receiving the combination; single agent OPDIVO was delayed in 37% of patients due to adverse reactions. The most common adverse reactions reported in ≥20% of patients treated with OPDIVO in combination with ipilimumab were fatigue, diarrhea, pruritus, abdominal pain, musculoskeletal pain, and nausea. The most common adverse reactions reported in ≥20% of patients treated with OPDIVO as a single agent, were fatigue, diarrhea, abdominal pain, pruritus, and musculoskeletal pain. Tables 40 and 41 summarize selected adverse reactions and selected laboratory abnormalities for OPDIVO in combination with ipilimumab and the single agent OPDIVO arms respectively, in CHECKMATE-8HW. Table 40: Adverse Reactions a in ≥10% in Patients with a Difference Between Arms of >5% for All Grades in CHECKMATE-8HW Toxicity was graded per NCI CTCAE v5. a Includes colitis, diarrhea, enterocolitis, immune mediated enterocolitis. Adverse Reaction OPDIVO and ipilimumab (n=352) OPDIVO (n=351) All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) Gastrointestinal Diarrhea a 35 4.5 30 3.4 Skin and Subcutaneous Tissue Pruritus 30 0 23 0 Musculoskeletal and Connective Tissue Arthralgia 20 0.6 15 0.6 Endocrine Hypothyroidism 18 0.6 10 0 Hyperthyroidism 12 0 5 0 Table 41: Laboratory Values Worsening from Baseline a in ≥10% of Patients and a Difference Between Arms of >5% for All Grades - CHECKMATE-8HW a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and ipilimumab group (range: 108 to 343 patients) or nivolumab group (range: 102 to 348 patients). Laboratory Abnormality a OPDIVO and Ipilimumab (n=352) OPDIVO (n=351) All Grades (%) Grades 3-or 4 (%) All Grades (%) Grades 3 or -4 (%) Hematology Lymphocytes decreased 30 5 37 4 Neutrophils decreased 21 1.7 12 0.6 Chemistry Lipase increased 44 10 32 11 Amylase increased 41 4.6 33 5 ALT increased 39 3.5 32 1.4 AST increased 38 3.2 29 1.4 Sodium decreased 36 3.2 30 2.3 Creatinine increased 32 2 25 1.4 Potassium increased 29 1.2 35 0.9 Glucose decreased 17 0 12 0 MSI-H or dMMR mCRC After Progression Following Treatment with a Fluoropyrimidine, Oxaliplatin, and Irinotecan The safety of OPDIVO administered as a single agent or in combination with ipilimumab was evaluated in CHECKMATE-142, a multicenter, non-randomized, multiple parallel-cohort, open-label trial [see Clinical Studies (14.11) ] . In CHECKMATE-142, 74 patients with mCRC received OPDIVO 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks until disease progression or until intolerable toxicity and 119 patients with mCRC received OPDIVO 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for 4 doses, then OPDIVO 3 mg/kg every 2 weeks until disease progression or until unacceptable toxicity. In the OPDIVO with ipilimumab cohort, serious adverse reactions occurred in 47% of patients. Treatment was discontinued in 13% of patients and delayed in 45% of patients for an adverse reaction. The most frequent serious adverse reactions reported in ≥2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. The most common adverse reactions (reported in ≥20% of patients) were fatigue, diarrhea, pyrexia, musculoskeletal pain, abdominal pain, pruritus, nausea, rash, decreased appetite, and vomiting. Tables 42 and 43 summarize adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-142. Based on the design of CHECKMATE-142, the data below cannot be used to identify statistically significant differences between the two cohorts summarized below for any adverse reaction. Table 42: Adverse Reactions Occurring in ≥10% of Patients - CHECKMATE-142 Toxicity was graded per NCI CTCAE v4. a Includes asthenia. b Includes peripheral edema and peripheral swelling. c Includes upper abdominal pain, lower abdominal pain, and abdominal discomfort. d Includes back pain, pain in extremity, myalgia, neck pain, and bone pain. e Includes dermatitis, dermatitis acneiform, and rash described as maculo-papular, erythematous, and generalized. f Includes nasopharyngitis and rhinitis. Adverse Reaction OPDIVO (n=74) OPDIVO and Ipilimumab (n=119) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General Fatigue a 54 5 49 6 Pyrexia 24 0 36 0 Edema b 12 0 7 0 Gastrointestinal Diarrhea 43 2.7 45 3.4 Abdominal pain c 34 2.7 30 5 Nausea 34 1.4 26 0.8 Vomiting 28 4.1 20 1.7 Constipation 20 0 15 0 Musculoskeletal and Connective Tissue Musculoskeletal pain d 28 1.4 36 3.4 Arthralgia 19 0 14 0.8 Respiratory, Thoracic and Mediastinal Cough 26 0 19 0.8 Dyspnea 8 1 13 1.7 Skin and Subcutaneous Tissue Rash e 23 1.4 25 4.2 Pruritus 19 0 28 1.7 Dry Skin 7 0 11 0 Infections Upper respiratory tract infection f 20 0 9 0 Endocrine Hyperglycemia 19 2.7 6 1 Hypothyroidism 5 0 14 0.8 Hyperthyroidism 4 0 12 0 Nervous System Headache 16 0 17 1.7 Dizziness 14 0 11 0 Metabolism and Nutrition Decreased appetite 14 1.4 20 1.7 Psychiatric Insomnia 9 0 13 0.8 Investigations Weight decreased 8 0 10 0 Clinically important adverse reactions reported in <10% of patients receiving OPDIVO with ipilimumab were encephalitis (0.8%), necrotizing myositis (0.8%), and uveitis (0.8%). Table 43: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥10% of Patients - CHECKMATE-142 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available. Number of evaluable patients ranges from 62 to 71 for the OPDIVO cohort and from 87 to 114 for the OPDIVO and ipilimumab cohort. Laboratory Abnormality OPDIVO (n=74) OPDIVO and Ipilimumab (n=119) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Hematology Anemia 50 7 42 9 Lymphopenia 36 7 25 6 Neutropenia 20 4.3 18 0 Thrombocytopenia 16 1.4 26 0.9 Chemistry Increased alkaline phosphatase 37 2.8 28 5 Increased lipase 33 19 39 12 Increased ALT 32 2.8 33 12 Increased AST 31 1.4 40 12 Hyponatremia 27 4.3 26 5 Hypocalcemia 19 0 16 0 Hypomagnesemia 17 0 18 0 Increased amylase 16 4.8 36 3.4 Increased bilirubin 14 4.2 21 5 Hypokalemia 14 0 15 1.8 Increased creatinine 12 0 25 3.6 Hyperkalemia 11 0 23 0.9 Hepatocellular Carcinoma Unresectable or Metastatic Hepatocellular Carcinoma (HCC) The safety of OPDIVO in combination with ipilimumab was evaluated in CHECKMATE-9DW, a randomized, open-label trial in adult patients with unresectable or metastatic HCC [see Clinical Studies (14.12) ] . Patients received OPDIVO in combination with ipilimumab (n=332) or investigator’s choice of lenvatinib (n=275) or sorafenib (n=50) at the following dosage: • OPDIVO 1 mg/kg administered intravenously over 30 minutes in combination with ipilimumab 3 mg/kg administered intravenously over 30 minutes every 3 weeks, for a maximum of 4 doses, followed by single-agent OPDIVO at 480 mg administered intravenously over 30 minutes every 4 weeks, or • Investigator’s choice: o Lenvatinib 8 mg orally daily (if body weight <60 kg) or 12 mg orally daily (if body weight ≥60 kg), or o Sorafenib 400 mg orally twice daily In the OPDIVO and ipilimumab arm, the median duration of exposure to OPDIVO was 4.7 months (range: <0.1 to 24.4 months), 45% were exposed for >6 months and 30% were exposed for >1 year. Serious adverse reactions occurred in 53% of patients treated with OPDIVO in combination with ipilimumab. The most frequent non-liver-related serious adverse reactions reported in ≥2% of patients who received OPDIVO in combination with ipilimumab were diarrhea/colitis (4.5%), gastrointestinal hemorrhage (3%), and rash (2.4%). Liver-related serious adverse reactions occurred in 17% of patients treated with OPDIVO in combination with ipilimumab, including Grade 3-4 events in 16% of patients. The most frequently reported all grade liver-related serious adverse reactions occurring in ≥1% of patients who received OPDIVO in combination with ipilimumab were immune-mediated hepatitis (3%), increased AST/ALT (3%), hepatic failure (2.4%), ascites (2.4%), and hepatotoxicity (1.2%). Fatal adverse reactions occurred in 12 (3.6%) patients who received OPDIVO in combination with ipilimumab; these included 4 (1.2%) patients who died due to immune-mediated or autoimmune hepatitis and 4 (1.2%) patients who died of hepatic failure. Permanent discontinuations of OPDIVO due to an adverse reaction occurred in 27% of patients. Adverse reactions leading to permanent discontinuation of OPDIVO in >1% of patients included immune-mediated hepatitis (1.8%), diarrhea/colitis (1.8%), hepatic failure (1.2%). Dosage interruptions of OPDIVO due to an adverse reaction occurred in 62% of patients. Adverse reactions which required dosage interruption in >5% of patients included increased AST (13%), increased ALT (11%), and diarrhea/colitis (8%). The most common (>20%) adverse reactions were rash, pruritus, fatigue, and diarrhea. Tables 44 and 45 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-9DW. Table 44: Adverse Reactions Occurring in ≥10% of OPDIVO in combination with Ipilimumab-Treated Patients - CHECKMATE-9DW Toxicity was graded per NCI CTCAE v5. a Represents a composite of multiple related terms. Adverse Reaction OPDIVO and Ipilimumab (n=332) Lenvatinib or Sorafenib (n=325) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Skin and Subcutaneous Tissue Rash a 36 3.6 15 1.2 Pruritus 34 1.5 7 0.3 General Fatigue a 33 2.4 39 4 Pyrexia a 15 0.6 9 1.5 Edema a 13 1.2 13 1.5 Gastrointestinal Diarrhea a 25 6 39 3.4 Abdominal pain a 14 1.2 27 2.5 Nausea 10 0.3 16 0.9 Musculoskeletal and Connective Tissue Musculoskeletal pain a 17 0.6 23 0.3 Arthralgia 12 0.3 13 0.6 Metabolism and Nutrition Decreased appetite 16 1.2 28 1.8 Endocrine Hypothyroidism a 14 0 27 0 Hyperthyroidism 11 0.6 1.5 0 Respiratory, Thoracic and Mediastinal Cough a 13 0 8 0 Clinically important adverse reactions reported in <10% of patients who received OPDIVO with ipilimumab were hyperglycemia (8%), adrenal insufficiency (4.2%), pneumonitis (2.7%), and pancreatitis (2.4%). Table 45: Laboratory Values Worsening from Baseline a Occurring in ≥20% of OPDIVO in combination with Ipilimumab-Treated Patients - CHECKMATE-9DW a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and ipilimumab group (range: 168 to 331 patients) and lenvatinib or sorafenib group (range: 145 to 315 patients). Laboratory Abnormality OPDIVO and Ipilimumab (n=332) Lenvatinib or Sorafenib (n=325) Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Chemistry Increased AST 62 29 51 14 Increased ALT 61 17 46 9 Increased lipase 58 16 39 5 Decreased albumin 48 0.9 57 0.6 Hyponatremia 45 6 42 3.8 Hyperglycemia 44 15 32 2.1 Increased bilirubin 44 10 44 8 Increased amylase 41 6 26 1 Increased alkaline phosphatase 36 1.2 38 5 Hypocalcemia 29 0.9 46 0 Increased creatinine 26 2.4 23 0.6 Hypokalemia 21 2.1 20 2.6 Hematology Anemia 44 5 40 3.8 Lymphopenia 40 6.1 40 8 Thrombocytopenia 27 4 44 4.8 Neutropenia 24 4 32 3.5 Previously Treated Hepatocellular Carcinoma The safety of OPDIVO 1 mg/kg in combination with ipilimumab 3 mg/kg was evaluated in a subgroup comprising 49 patients with HCC and Child-Pugh Class A cirrhosis enrolled in Cohort 4 of CHECKMATE-040, a multicenter, multiple-cohort, open-label trial [see Clinical Studies (14.12) ] who progressed on or were intolerant to sorafenib. OPDIVO and ipilimumab were administered every 3 weeks for 4 doses, followed by single-agent OPDIVO 240 mg every 2 weeks until disease progression or unacceptable toxicity. During the OPDIVO and ipilimumab combination period, 33 of 49 (67%) patients received all 4 planned doses of OPDIVO and ipilimumab. During the entire treatment period, the median duration of exposure to OPDIVO was 5.1 months (range: 0 to 35+ months) and to ipilimumab was 2.1 months (range: 0 to 4.5 months). Forty-seven percent of patients were exposed to treatment for >6 months, and 35% of patients were exposed to treatment for >1 year. Serious adverse reactions occurred in 59% of patients. Treatment was discontinued in 29% of patients and delayed in 65% of patients for an adverse reaction. The most frequent serious adverse reactions (reported in ≥4% of patients) were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis. Tables 46 and 47 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-040. Table 46: Adverse Reactions Occurring in ≥10% of Patients Receiving OPDIVO in Combination with Ipilimumab in Cohort 4 of CHECKMATE-040 Adverse Reaction OPDIVO and Ipilimumab (n=49) All Grades (%) Grades 3-4 (%) Skin and Subcutaneous Tissue Rash 53 8 Pruritus 53 4 Musculoskeletal and Connective Tissue Musculoskeletal pain 41 2 Arthralgia 10 0 Gastrointestinal Diarrhea 39 4 Abdominal pain 22 6 Nausea 20 0 Ascites 14 6 Constipation 14 0 Dry mouth 12 0 Dyspepsia 12 2 Vomiting 12 2 Stomatitis 10 0 Respiratory, Thoracic and Mediastinal Cough 37 0 Dyspnea 14 0 Pneumonitis 10 2 Metabolism and Nutrition Decreased appetite 35 2 General Fatigue 27 2 Pyrexia 27 0 Malaise 18 2 Edema 16 2 Influenza-like illness 14 0 Chills 10 0 Nervous System Headache 22 0 Dizziness 20 0 Endocrine Hypothyroidism 20 0 Adrenal insufficiency 18 4 Investigations Weight decreased 20 0 Psychiatric Insomnia 18 0 Blood and Lymphatic System Anemia 10 4 Infections Influenza 10 2 Vascular Hypotension 10 0 Clinically important adverse reactions reported in <10% of patients who received OPDIVO with ipilimumab were hyperglycemia (8%), colitis (4%), and increased blood creatine phosphokinase (2%). Table 47: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients Receiving OPDIVO in Combination with Ipilimumab in Cohort 4 of CHECKMATE-040 Laboratory Abnormality OPDIVO and Ipilimumab (n=47) All Grades (%) Grades 3-4 (%) Hematology Lymphopenia 53 13 Anemia 43 4.3 Neutropenia 43 9 Leukopenia 40 2.1 Thrombocytopenia 34 4.3 Chemistry Increased AST 66 40 Increased ALT 66 21 Increased bilirubin 55 11 Increased lipase 51 26 Hyponatremia 49 32 Hypocalcemia 47 0 Increased alkaline phosphatase 40 4.3 Increased amylase 38 15 Hypokalemia 26 2.1 Hyperkalemia 23 4.3 Increased creatinine 21 0 Hypomagnesemia 11 0 In patients who received OPDIVO with ipilimumab, virologic breakthrough occurred in 4 of 28 (14%) patients and 2 of 4 (50%) patients with active HBV or HCV at baseline, respectively. HBV virologic breakthrough was defined as at least a 1 log increase in HBV DNA for those patients with detectable HBV DNA at baseline. HCV virologic breakthrough was defined as a 1 log increase in HCV RNA from baseline. Esophageal Cancer Adjuvant Treatment of Resected Esophageal or Gastroesophageal Junction Cancer The safety of OPDIVO was evaluated in CHECKMATE-577, a randomized, placebo-controlled, double-blinded, multicenter trial in 792 treated patients with completely resected (negative margins) esophageal or gastroesophageal junction cancer who had residual pathologic disease following chemoradiotherapy (CRT) [see Clinical Studies (14.13) ] . The trial excluded patients who did not receive concurrent CRT prior to surgery, had stage IV resectable disease, autoimmune disease, or any condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications. Patients received either OPDIVO 240 mg or placebo by intravenous infusion over 30 minutes every 2 weeks for 16 weeks followed by 480 mg or placebo by intravenous infusion over 30 minutes every 4 weeks beginning at week 17. Patients were treated until disease recurrence, unacceptable toxicity, or for up to 1-year total duration. The median duration of exposure was 10.1 months (range: <0.1 to 14 months) in OPDIVO-treated patients and 9 months (range: <0.1 to 15 months) in placebo-treated patients. Among patients who received OPDIVO, 61% were exposed for >6 months and 54% were exposed for >9 months. Serious adverse reactions occurred in 33% of patients receiving OPDIVO. A serious adverse reaction reported in ≥2% of patients who received OPDIVO was pneumonitis. A fatal adverse reaction of myocardial infarction occurred in one patient who received OPDIVO. OPDIVO was discontinued in 12% of patients and was delayed in 28% of patients for an adverse reaction. Tables 48 and 49 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-577. Table 48: Adverse Reactions Occurring in ≥10% of Patients Receiving OPDIVO - CHECKMATE-577 a Includes upper abdominal pain, lower abdominal pain, and abdominal discomfort. b Includes gastroesophageal reflux. c Includes asthenia. d Includes productive cough. e Includes dyspnea exertional. f Includes rash pustular, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, exfoliative rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic. g Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, myalgia intercostal, neck pain, pain in extremity, spinal pain. Adverse Reaction OPDIVO (n=532) Placebo (n=260) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Adverse Reaction 96 34 93 32 Gastrointestinal Diarrhea 29 0.9 29 0.8 Nausea 23 0.8 21 0 Abdominal Pain a 17 0.8 20 1.5 Vomiting 15 0.6 16 1.2 Dysphagia 13 0.8 17 3.5 Dyspepsia b 12 0.2 16 0.4 Constipation 11 0 12 0 General Fatigue c 34 1.3 29 1.5 Respiratory, Thoracic and Mediastinal Cough d 20 0.2 21 0.4 Dyspnea e 12 0.8 12 0.4 Skin and Subcutaneous Tissue Rash f 21 0.9 10 0.4 Pruritus 13 0.4 6 0 Investigations Weight decreased 13 0.4 9 0 Musculoskeletal and Connective Tissue Musculoskeletal pain g 21 0.6 20 0.8 Arthralgia 10 0.2 8 0 Metabolism and Nutrition Decreased appetite 15 0.9 10 0.8 Endocrine Hypothyroidism 11 0 1.5 0 Table 49: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥10% of Patients - CHECKMATE-577 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (range: 163 to 526 patients) and Placebo group (range: 86 to 256 patients). b Includes alanine aminotransferase increased, aspartate aminotransferase increased. Laboratory Abnormality OPDIVO (n=532) Placebo (n=260) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Chemistry Increased AST 27 2.1 22 0.8 Increased alkaline phosphatase 25 0.8 18 0.8 Increased albumin 21 0.2 18 0 Increased ALT 20 1.9 16 1.2 Increased amylase 20 3.9 13 1.3 Hyponatremia 19 1.7 12 1.2 Hyperkalemia 17 0.8 15 1.6 Hypokalemia 12 1 11 1.2 Transaminases increased b 11 1.5 6 1.2 Hematology Lymphopenia 44 17 35 12 Anemia 27 0.8 21 0.4 Neutropenia 24 1.5 23 0.4 First-line Treatment of Unresectable Advanced or Metastatic ESCC The safety of OPDIVO in combination with chemotherapy or in combination with ipilimumab was evaluated in CHECKMATE-648, a randomized, active-controlled, multicenter, open-label trial in patients with previously untreated unresectable advanced, recurrent or metastatic ESCC [see Clinical Studies (14.13) ]. Patients received one of the following treatments: • OPDIVO 240 mg on days 1 and 15, 5-FU (fluorouracil) 800 mg/m 2 /day intravenously on days 1 through 5 (for 5 days), and cisplatin 80 mg/m 2 intravenously on day 1 (of a 4-week cycle). • OPDIVO 3 mg/kg every 2 weeks in combination with ipilimumab 1 mg/kg every 6 weeks. • 5-FU (fluorouracil) 800 mg/m 2 /day intravenously on days 1 through 5 (for 5 days), and cisplatin 80 mg/m 2 intravenously on day 1 (of a 4-week cycle). Among patients who received OPDIVO with chemotherapy, the median duration of exposure was 5.7 months (range: 0.1 to 30.6 months). Among patients who received OPDIVO and ipilimumab, the median duration of exposure was 2.8 months (range: 0 to 24 months). Serious adverse reactions occurred in 62% of patients receiving OPDIVO in combination with chemotherapy and in 69% of patients receiving OPDIVO in combination with ipilimumab. The most frequent serious adverse reactions reported in ≥2% of patients who received OPDIVO with chemotherapy were pneumonia (11%), dysphagia (7%), esophageal stenosis (2.9%), acute kidney injury (2.9%), and pyrexia (2.3%). The most frequent serious adverse reactions reported in ≥2% of patients who received OPDIVO with ipilimumab were pneumonia (10%), pyrexia (4.3%), pneumonitis (4%), aspiration pneumonia (3.7%), dysphagia (3.7%), hepatic function abnormal (2.8%), decreased appetite (2.8%), adrenal insufficiency (2.5%), and dehydration (2.5%). Fatal adverse reactions occurred in 5 (1.6%) patients who received OPDIVO in combination with chemotherapy; these included pneumonitis, pneumatosis intestinalis, pneumonia, and acute kidney injury and in 5 (1.6%) patients who received OPDIVO in combination with ipilimumab; these included pneumonitis, interstitial lung disease, pulmonary embolism, and acute respiratory distress syndrome. OPDIVO and/or chemotherapy were discontinued in 39% of patients and were delayed in 71% of patients for an adverse reaction. OPDIVO and/or ipilimumab were discontinued in 23% of patients and were delayed in 46% of patients for an adverse reaction. The most common adverse reactions reported in ≥20% of patients treated with OPDIVO in combination with chemotherapy were nausea, decreased appetite, fatigue, constipation, stomatitis, diarrhea, and vomiting. The most common adverse reactions reported in ≥20% of patients treated with OPDIVO in combination with ipilimumab were rash, fatigue, pyrexia, nausea, diarrhea, and constipation. Tables 50 and 51 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-648. Table 50: Adverse Reactions in ≥10% of Patients - CHECKMATE-648 Toxicity was graded per NCI CTCAE v4. a Includes aphthous ulcer, mouth ulceration, and mucosal inflammation. b Includes abdominal discomfort, abdominal pain lower, and abdominal pain upper. c Includes asthenia and malaise. d Includes tumor associated fever. e Includes swelling, generalized edema, edema peripheral, and peripheral swelling. f Includes hyperesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, and peripheral sensory neuropathy. g Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, drug eruption, exfoliative rash, rash erythematous, rash follicular, rash macular, rash maculo-papular, rash papular, and rash pruritic. h Includes productive cough. i Includes organizing pneumonia, pneumonia bacterial, and pneumonia pseudomonal. j Includes back pain, bone pain, musculoskeletal chest pain, myalgia, neck pain, pain in extremity, and spinal pain. Adverse Reaction OPDIVO with Cisplatin and 5‑FU (n=310) OPDIVO and Ipilimumab (n=322) Cisplatin and 5-FU (n=304) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Gastrointestinal Nausea 65 4.2 22 0.6 56 2.6 Constipation 44 1.0 20 0.3 43 1 Stomatitis a 44 9 11 0.6 35 3 Diarrhea 29 2.9 22 1.9 20 2 Vomiting 23 2.3 15 1.6 19 3 Dysphagia 14 7 12 5 12 4.9 Abdominal pain b 13 1.9 10 0.9 11 0.7 Metabolism and Nutrition Decreased appetite 51 7 17 4 50 6 General Fatigue c 47 3.5 28 2.5 41 4.9 Pyrexia d 19 0.3 23 0.9 12 0.3 Edema e 16 0 7 0 13 0 Nervous System Peripheral neuropathy f 18 1.3 2.8 0 13 1 Psychiatric Insomnia 16 0 8 0 10 0.3 Skin and Subcutaneous Tissue Rash g 16 0.6 31 3.1 7 0 Pruritus 11 0 17 0.9 3.6 0 Alopecia 10 0 11 0 Respiratory, Thoracic and Mediastinal Cough h 16 0.3 13 0.3 13 0.3 Infections and Infestations Pneumonia i 13 5 14 8 10 2.6 Endocrine Hypothyroidism 7 0 14 0 0.3 0 Investigations Weight decreased 12 0.6 12 1.9 11 1 Musculoskeletal and Connective Tissue Musculoskeletal pain j 11 0.3 14 0.6 8 0.3 Table 51: Laboratory Values Worsening from Baseline a Occurring in ≥10% of Patients - CHECKMATE-648 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO with cisplatin and 5-FU group (range: 60 to 305 patients), OPDIVO and ipilimumab group (range: 59 to 307 patients) or cisplatin and 5-FU group (range: 56 to 283 patients). Laboratory Abnormality OPDIVO with Cisplatin and 5-FU (n=310) OPDIVO and Ipilimumab (n=322) Cisplatin and 5-FU (n=304) Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Hematology Anemia 81 21 52 7 66 14 Lymphopenia 67 23 50 13 44 8 Neutropenia 61 18 13 1.3 48 13 Leukopenia 53 11 39 5 Thrombocytopenia 43 3.3 12 1 29 2.8 Chemistry Hyponatremia 52 15 45 11 40 8 Hypocalcemia 43 3 32 0 23 0.7 Increased creatinine 41 2.3 15 0.7 31 0.7 Hypomagnesemia 35 1.7 15 0 25 1.8 Hyperglycemia 34 0 43 4.3 36 0.8 Hyperkalemia 33 2.3 23 1.6 24 0.7 Hypokalemia 29 9 19 5 17 6 Increased alkaline phosphatase 26 1.3 31 3.3 15 0 Increased AST 23 3.3 39 6 11 1.4 Increased ALT 23 2.3 33 6 8 0.7 Hypoglycemia 18 0.4 15 1.2 7 0 Hypercalcemia 11 2.6 15 2 8 0 Previously-Treated Unresectable Advanced, Recurrent or Metastatic Esophageal Squamous Cell Carcinoma (ESCC) The safety of OPDIVO was evaluated in ATTRACTION-3, a randomized, active-controlled, open-label, multicenter trial in 209 patients with unresectable advanced, recurrent or metastatic ESCC refractory or intolerant to at least one fluoropyrimidine- and platinum-based chemotherapy [see Clinical Studies (14.13) ]. The trial excluded patients who were refractory or intolerant to taxane therapy, had brain metastases that were symptomatic or required treatment, had autoimmune disease, used systemic corticosteroids or immunosuppressants, had apparent tumor invasion of organs adjacent to the esophageal tumor or had stents in the esophagus or respiratory tract. Patients received OPDIVO 240 mg by intravenous infusion over 30 minutes every 2 weeks (n=209) or investigator’s choice: docetaxel 75 mg/m 2 intravenously every 3 weeks (n=65) or paclitaxel 100 mg/m 2 intravenously once a week for 6 weeks followed by 1 week off (n=143). Patients were treated until disease progression or unacceptable toxicity. The median duration of exposure was 2.6 months (range: 0 to 29.2 months) in OPDIVO-treated patients and 2.6 months (range: 0 to 21.4 months) in docetaxel- or paclitaxel-treated patients. Among patients who received OPDIVO, 26% were exposed for >6 months and 10% were exposed for >1 year. Serious adverse reactions occurred in 38% of patients receiving OPDIVO. Serious adverse reactions reported in ≥2% of patients who received OPDIVO were pneumonia, esophageal fistula, interstitial lung disease and pyrexia. The following fatal adverse reactions occurred in patients who received OPDIVO: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%). OPDIVO was discontinued in 13% of patients and was delayed in 27% of patients for an adverse reaction. Tables 52 and 53 summarize the adverse reactions and laboratory abnormalities, respectively, in ATTRACTION-3. Table 52: Adverse Reactions Occurring in ≥10% of Patients Receiving OPDIVO - ATTRACTION-3 Toxicity was graded per NCI CTCAE v4. a Includes urticaria, drug eruption, eczema, eczema asteatotic, eczema nummular, palmar-plantar erythrodysesthesia syndrome, erythema, erythema multiforme, blister, skin exfoliation, Stevens-Johnson syndrome, dermatitis, dermatitis described as acneiform, bullous, or contact, and rash described as maculo-papular, generalized, or pustular. b Includes hypophagia, and food aversion. c Includes colitis. d Includes spondylolisthesis, periarthritis, musculoskeletal chest pain, neck pain, arthralgia, back pain, myalgia, pain in extremity, arthritis, bone pain, and periarthritis calcarea. e Includes influenza, influenza like illness, pharyngitis, nasopharyngitis, tracheitis, and bronchitis and upper respiratory infection with bronchitis. f Includes pneumonia aspiration, pneumonia bacterial, and lung infection. Two patients (1.0%) died of pneumonia in the OPDIVO treatment arm. Two patients (1.0%) died of pneumonia in the chemotherapy treatment arm; these deaths occurred with paclitaxel only. g Includes productive cough. h Includes tumor-associated fever. i Includes asthenia. j Includes hemoglobin decreased, and iron deficiency anemia. k Includes blood thyroid stimulating hormone increased. Adverse Reaction OPDIVO (n=209) Docetaxel or Paclitaxel (n=208) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Skin and Subcutaneous Tissue Rash a 22 1.9 28 1 Pruritus 12 0 7 0 Metabolism and Nutrition Decreased appetite b 21 1.9 35 5 Gastrointestinal Diarrhea c 18 1.9 17 1.4 Constipation 17 0 19 0 Nausea 11 0 20 0.5 Musculoskeletal and Connective Tissue Musculoskeletal pain d 17 0 26 1.4 Infections Upper respiratory tract infection e 17 1 14 0 Pneumonia f 13 5 19 9 Respiratory, Thoracic and Mediastinal Cough g 16 0 14 0.5 General Pyrexia h 16 0.5 19 0.5 Fatigue i 12 1.4 27 4.8 Blood and Lymphatic System Anemia j 13 8 30 13 Endocrine Hypothyroidism k 11 0 1.4 0 Table 53: Laboratory Abnormalities Worsening from Baseline a Occurring in ≥10% of Patients - ATTRACTION-3 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO group (209 patients) and Docetaxel or Paclitaxel group (range: 207 to 208 patients). Laboratory Abnormality OPDIVO (n=209) Docetaxel or Paclitaxel (n=208) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Chemistry Increased creatinine 78 0.5 68 0.5 Hyperglycemia 52 5 62 5 Hyponatremia 42 11 50 12 Increased AST 40 6 30 1 Increased alkaline phosphatase 33 4.8 24 1.0 Increased ALT 31 5 22 1.9 Hypercalcemia 22 6 14 2.9 Hyperkalemia 22 0.5 31 1 Hypoglycemia 14 1.4 14 0.5 Hypokalemia 11 2.9 13 3.4 Hematology Lymphopenia 46 19 72 43 Anemia 42 9 71 17 Leukopenia 11 0.5 79 45 Gastric Cancer, Gastroesophageal Junction Cancer, and Esophageal Adenocarcinoma The safety of OPDIVO in combination with chemotherapy was evaluated in CHECKMATE-649, a randomized, multicenter, open-label trial in patients with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma [see Clinical Studies (14.14) ] . The trial excluded patients who were known human epidermal growth factor receptor 2 (HER2) positive or had untreated central nervous system (CNS) metastases. Patients were randomized to receive OPDIVO in combination with chemotherapy or chemotherapy. Patients received one of the following treatments: • OPDIVO 240 mg in combination with mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) every 2 weeks or mFOLFOX6 every 2 weeks. • OPDIVO 360 mg in combination with CapeOX (capecitabine and oxaliplatin) every 3 weeks or CapeOX every 3 weeks. Patients were treated with OPDIVO in combination with chemotherapy or chemotherapy until disease progression, unacceptable toxicity, or up to 2 years. The median duration of exposure was 6.8 months (range: 0 to 33.5 months) in OPDIVO and chemotherapy-treated patients. Among patients who received OPDIVO and chemotherapy, 54% were exposed for >6 months and 28% were exposed for >1 year. Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with OPDIVO in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation. Serious adverse reactions occurred in 52% of patients treated with OPDIVO in combination with chemotherapy. OPDIVO and/or chemotherapy were discontinued in 44% of patients and at least one dose was withheld in 76% of patients due to an adverse reaction. The most frequent serious adverse reactions reported in ≥2% of patients treated with OPDIVO in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). The most common adverse reactions reported in ≥20% of patients treated with OPDIVO in combination with chemotherapy were peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain. Tables 54 and 55 summarize the adverse reactions and laboratory abnormalities, respectively, in CHECKMATE-649. Table 54: Adverse Reactions in ≥10% of Patients Receiving OPDIVO and Chemotherapy - CHECKMATE-649 Toxicity was graded per NCI CTCAE v4. a Includes dysesthesia, hypoesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, and peripheral sensory neuropathy. b Includes abdominal discomfort, abdominal pain lower, and abdominal pain upper. c Includes aphthous ulcer, mouth ulceration, and mucosal inflammation. d Includes asthenia. e Includes tumor associated fever. f Includes swelling, generalized edema, edema peripheral, and peripheral swelling. g Includes blood albumin decreased. h Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, and spinal pain. i Includes dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, drug eruption, exfoliative rash, nodular rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash vesicular. j Includes productive cough. k Includes nasopharyngitis, pharyngitis, and rhinitis. Adverse Reaction OPDIVO and mFOLFOX6 or CapeOX (n=782) mFOLFOX6 or CapeOX (n=767) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Adverse Reaction 99 69 98 59 Nervous System Peripheral neuropathy a 53 7 46 4.8 Headache 11 0.8 6 0.3 Gastrointestinal Nausea 48 3.2 44 3.7 Diarrhea 39 5 34 3.7 Vomiting 31 4.2 29 4.2 Abdominal pain b 27 2.8 24 2.6 Constipation 25 0.6 21 0.4 Stomatitis c 17 1.8 13 0.8 General Fatigue d 44 7 40 5 Pyrexia e 19 1 11 0.4 Edema f 12 0.5 8 0.1 Metabolism and Nutrition Decreased appetite 29 3.6 26 2.5 Hypoalbuminemia g 14 0.3 9 0.3 Investigations Weight decreased 17 1.3 15 0.7 Increased lipase 14 7 8 3.7 Increased amylase 12 3.1 5 0.4 Musculoskeletal and Connective Tissue Musculoskeletal pain h 20 1.3 14 2 Skin and Subcutaneous Tissue Rash i 18 1.7 4.4 0.1 Palmar-plantar erythrodysesthesia syndrome 13 1.5 12 0.8 Respiratory, Thoracic and Mediastinal Cough j 13 0.1 9 0 Infections and Infestations Upper respiratory tract infection k 10 0.1 7 0.1 Table 55: Laboratory Values Worsening from Baseline a Occurring in ≥10% of Patients - CHECKMATE-649 a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: OPDIVO and mFOLFOX6 or CapeOX group (407 to 767 patients) or mFOLFOX6 or CapeOX group (range: 405 to 735 patients). Laboratory Abnormality OPDIVO and mFOLFOX6 or CapeOX (n=782) mFOLFOX6 or CapeOX (n=767) Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Hematology Neutropenia 73 29 62 23 Leukopenia 69 12 59 9 Thrombocytopenia 68 7 63 4.4 Anemia 59 14 60 10 Lymphopenia 59 12 49 9 Chemistry Increased AST 52 4.6 47 1.9 Hypocalcemia 42 1.6 37 1 Hyperglycemia 41 3.9 38 2.7 Increased ALT 37 3.4 30 1.9 Hyponatremia 34 6 24 5 Hypokalemia 27 7 24 4.8 Hyperbilirubinemia 24 2.8 21 2 Increased creatinine 15 1 9 0.5 Hyperkalemia 14 1.4 11 0.7 Hypoglycemia 12 0.7 9 0.2 Hypernatremia 11 0.5 7.1 0 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of OPDIVO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Eye: Vogt-Koyanagi-Harada (VKH) syndrome Complications of OPDIVO Treatment After Allogeneic HSCT: Treatment refractory, severe acute and chronic GVHD Blood and lymphatic system disorders: Hemophagocytic lymphohistiocytosis (HLH) (including fatal cases), autoimmune hemolytic anemia (including fatal cases) Metabolism and nutrition disorders: tumor lysis syndrome

8.1 Pregnancy Risk Summary Based on data from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , OPDIVO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death (see Data) . Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus. The effects of OPDIVO are likely to be greater during the second and third trimesters of pregnancy. There are no available data on OPDIVO use in pregnant women to evaluate a drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis through delivery, at exposure levels of between 9 and 42 times higher than those observed at the clinical dose of 3 mg/kg (based on AUC). Nivolumab administration resulted in a non-dose-related increase in spontaneous abortion and increased neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period.